AKAP12

Gene Summary

Gene:AKAP12; A kinase (PRKA) anchor protein 12
Aliases: SSeCKS, AKAP250
Location:6q24-q25
Summary:The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is expressed in endothelial cells, cultured fibroblasts, and osteosarcoma cells. It associates with protein kinases A and C and phosphatase, and serves as a scaffold protein in signal transduction. This protein and RII PKA colocalize at the cell periphery. This protein is a cell growth-related protein. Antibodies to this protein can be produced by patients with myasthenia gravis. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:A-kinase anchor protein 12
HPRD
Source:NCBIAccessed: 11 August, 2015

Ontology:

What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer DNA
  • Computational Biology
  • Skin Cancer
  • Neoplastic Cell Transformation
  • Leukaemia
  • Messenger RNA
  • Adolescents
  • Cell Cycle Proteins
  • Gene Silencing
  • Cancer Gene Expression Regulation
  • Tumor Suppressor Gene
  • Staging
  • Azacitidine
  • Case-Control Studies
  • CpG Islands
  • Polymerase Chain Reaction
  • Lung Cancer
  • Colonic Neoplasms
  • Chromosome 6
  • Protein Array Analysis
  • A Kinase Anchor Proteins
  • Colorectal Cancer
  • Epigenetics
  • Gene Expression Profiling
  • DNA Methylation
  • Western Blotting
  • Base Sequence
  • MMP9
  • Down-Regulation
  • Xenograft Models
  • Signal Transduction
  • Myeloid Leukemia
  • Up-Regulation
  • Adenocarcinoma
  • Enzyme Inhibitors
  • RTPCR
  • Promoter Regions
  • Neoplasm Metastasis
  • Young Adult
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AKAP12 (cancer-related)

Finger EC, Castellini L, Rankin EB, et al.
Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells.
Proc Natl Acad Sci U S A. 2015; 112(14):4441-6 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (A-kinase anchor protein 12), AKAP12v2, in metastatic melanoma. In turn, through a kinome-wide phosphoproteomic and MS study, we demonstrate that this scaffolding protein regulates a shift in protein kinase A (PKA)-mediated phosphorylation events under hypoxia, causing alterations in tumor cell invasion and migration in vitro, as well as metastasis in an in vivo orthotopic model of melanoma. Mechanistically, the shift in AKAP12-dependent PKA-mediated phosphorylations under hypoxia is due to changes in AKAP12 localization vs. structural differences between its two variants. Importantly, our work defines a mechanism through which a scaffold protein can be regulated by the tumor microenvironment and further explains how a tumor cell can coordinate many critical signaling pathways that are essential for tumor growth through one individual scaffolding protein.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Lopez-Ayllon BD, Moncho-Amor V, Abarrategi A, et al.
Cancer stem cells and cisplatin-resistant cells isolated from non-small-lung cancer cell lines constitute related cell populations.
Cancer Med. 2014; 3(5):1099-111 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
Lung cancer is the top cause of cancer-related deceases. One of the reasons is the development of resistance to the chemotherapy treatment. In particular, cancer stem cells (CSCs), can escape treatment and regenerate the bulk of the tumor. In this article, we describe a comparison between cancer cells resistant to cisplatin and CSCs, both derived from the non-small-cell lung cancer cell lines H460 and A549. Cisplatin-resistant cells were obtained after a single treatment with the drug. CSCs were isolated by culture in defined media, under nonadherent conditions. The isolated CSCs were clonogenic, could be differentiated into adherent cells and were less sensitive to cisplatin than the original cells. Cisplatin resistant and CSCs were able to generate primary tumors and to metastasize when injected into immunodeficient Nu/Nu mice, although they formed smaller tumors with a larger latency than untreated cells. Notably, under appropriated proportions, CSCs synergized with differentiated cells to form larger tumors. CSCs also showed increased capacity to induce angiogenesis in Nu/Nu mice. Conversely, H460 cisplatin-resistant cells showed increased tendency to develop bone metastasis. Gene expression analysis showed that several genes involved in tumor development and metastasis (EGR1, COX2, MALAT1, AKAP12, ADM) were similarly induced in CSC and cisplatin-resistant H460 cells, in agreement with a close similarity between these two cell populations. Cells with the characteristic growth properties of CSCs were also isolated from surgical samples of 18 out of 44 lung cancer patients. A significant correlation (P = 0.028) was found between the absence of CSCs and cisplatin sensitivity.

Ko HK, Akakura S, Peresie J, et al.
A transgenic mouse model for early prostate metastasis to lymph nodes.
Cancer Res. 2014; 74(3):945-53 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12 or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia. Here, we show that the combined loss of Akap12 and Rb results in prostatic intraepithelial neoplasia (PIN) that fails to progress to malignancy after 18 months. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal (p63, cytokeratin 14) and luminal (cytokeratin 8 and androgen receptor) epithelial cells, although none expressed the basal marker, cytokeratin 5. The finding that PIN lesions contain increased numbers of p63/AR-positive, cytokeratin 5-negative basal cells compared with WT or Akap12-/- prostate lobes suggests that these transitional cells may be the source of the lymph node metastases. Taken together, these data suggest that in the context of Rb loss, Akap12 suppresses the oncogenic proliferation and early metastatic spread of basal-luminal prostate tumor cells.

Pagnotta SM, Laudanna C, Pancione M, et al.
Ensemble of gene signatures identifies novel biomarkers in colorectal cancer activated through PPARγ and TNFα signaling.
PLoS One. 2013; 8(8):e72638 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
We describe a novel bioinformatic and translational pathology approach, gene Signature Finder Algorithm (gSFA) to identify biomarkers associated with Colorectal Cancer (CRC) survival. Here a robust set of CRC markers is selected by an ensemble method. By using a dataset of 232 gene expression profiles, gSFA discovers 16 highly significant small gene signatures. Analysis of dichotomies generated by the signatures results in a set of 133 samples stably classified in good prognosis group and 56 samples in poor prognosis group, whereas 43 remain unreliably classified. AKAP12, DCBLD2, NT5E and SPON1 are particularly represented in the signatures and selected for validation in vivo on two independent patients cohorts comprising 140 tumor tissues and 60 matched normal tissues. Their expression and regulatory programs are investigated in vitro. We show that the coupled expression of NT5E and DCBLD2 robustly stratifies our patients in two groups (one of which with 100% survival at five years). We show that NT5E is a target of the TNF-α signaling in vitro; the tumor suppressor PPARγ acts as a novel NT5E antagonist that positively and concomitantly regulates DCBLD2 in a cancer cell context-dependent manner.

Zhu XQ, Hu ML, Zhang F, et al.
Expression profiling based on graph-clustering approach to determine colon cancer pathway.
J Cancer Res Ther. 2013 Jul-Sep; 9(3):467-70 [PubMed] Related Publications
CONTEXT: Colorectal cancer is the second leading cause of cancer deaths worldwide. DNA microarray-based technologies allow simultaneous analysis of expression of thousands of genes.
AIM: To search for important molecular markers and pathways that hold great promise for further treatment of patients with colorectal cancer.
MATERIALS AND METHODS: Here, we performed a comprehensive gene-level assessment of colorectal cancer using 35 colorectal cancer and 24 normal samples.
RESULTS: It was shown that AURKA, MT1G, and AKAP12 had a high degree of response in colorectal cancer. Besides, we further explored the underlying molecular mechanism within these different genes.
CONCLUSIONS: The results indicated calcium signaling pathway and vascular smooth muscle contraction pathway were the two significant pathways, giving hope to provide insights into the development of novel therapeutic targets and pathways.

Yildirim M, Suren D, Yildiz M, et al.
AKAP12/Gravin gene expression in colorectal cancer: clinical importance and review of the literature.
J BUON. 2013 Jul-Sep; 18(3):635-40 [PubMed] Related Publications
PURPOSE: : Colorectal cancer (CRC) is a common and potentially lethal disease. A number of genetic aberrations is known to take place in colorectal carcinogenesis, which leads to progressive alteration of normal mechanisms controlling cell growth. A-kinase-anchoring protein 12 (AKAP12) plays a role in cell proliferation, angiogenesis and cytoskeletal remodeling. The purpose of this study was to demonstrate the role of the AKAP12 gene expression in CRC patients and to determine its relationship (if any) with prognosis.
METHODS: AKAP12 gene expression was investigated by immunohistochemistry.
RESULTS: A total of 55 patients (63.6% males, 36.4% females) with histologically confirmed CRC were studied. Normal intestinal epithelium showed weak basal staining, dysplastic areas were stained mildly, whereas all of the cancer cells were stained completely with AKAP12.
CONCLUSION: AKAP12 gene seems to play a role in colorectal carcinogenesis.

Goeppert B, Schmidt CR, Geiselhart L, et al.
Differential expression of the tumor suppressor A-kinase anchor protein 12 in human diffuse and pilocytic astrocytomas is regulated by promoter methylation.
J Neuropathol Exp Neurol. 2013; 72(10):933-41 [PubMed] Related Publications
The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY® of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12α promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2'-deoxycytidine in primary glioblastoma cells decreased AKAP12α promoter methylation and markedly increased AKAP12α mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined.

Lin ZY, Wu CC, Chuang YH, Chuang WL
Anti-cancer mechanisms of clinically acceptable colchicine concentrations on hepatocellular carcinoma.
Life Sci. 2013; 93(8):323-8 [PubMed] Related Publications
AIMS: This study was to investigate whether the clinically acceptable colchicine concentrations had anti-cancer effects on hepatocellular carcinoma (HCC) and their anti-cancer mechanisms.
MAIN METHODS: Two human HCC cell lines (HCC24/KMUH, HCC38/KMUH) and two human cancer-associated fibroblast (CAF) cell lines (F28/KMUH, F59/KMUH) were investigated by proliferative assay, microarray, quantitative reverse transcriptase-polymerase chain reaction, and nude mouse study using clinically acceptable colchicine concentrations.
KEY FINDINGS: Both 2 and 6ng/mL colchicine significantly inhibited the cellular proliferation of all cell lines tested (P<0.05). The anti-proliferative effects of colchicine on F28/KMUH, HCC24/KMUH and HCC38/KMUH cells were dose-dependent. The anti-proliferative effects of 6ng/mL colchicine on both HCC cell lines were similar to the effects of 1μg/mL epirubicin. The anti-proliferative effects of colchicine on HCC cells could be partially explained by dose-dependent up-regulations of 2 anti-proliferative genes (AKAP12, TGFB2) in these cells. TGFB2 was also up-regulated in CAFs but was not dose-dependent. Up-regulation of MX1 which can accelerate cell death was a common effect of 6ng/mL colchicine on both CAF cell lines, but 2ng/mL colchicine down-regulated MX1 in F28/KMUH cells. Nude mouse (BALB/c-nu) experiment showed that colchicine-treated mice (0.07mgcolchicine/kg/day×14days) had lower increased tumor volume ratios, slower tumor growth rates and larger percentages of tumor necrotic areas than control mice (all P<0.05).
SIGNIFICANCE: Clinically acceptable colchicine concentrations have anti-cancer effects on HCC. This drug has potential for the palliative treatment of HCC.

Mostafa MR, Yahia RS, Abd El Messih HM, et al.
Gravin gene expression in acute myeloid leukemia.
Med Oncol. 2013; 30(2):548 [PubMed] Related Publications
Acute leukemias are caused by genetic and epigenetic mechanisms involving tumor suppressor genes and oncogenes. Aberrant DNA methylation patterns are the most frequent molecular alterations detected in acute myeloid leukemia (AML). Gravin is down-regulated in several solid tumors and is implicated in tumorigenesis. To explore its role in the molecular pathogenesis and its possible prognostic importance in AML, we have evaluated the expression levels of the gravin gene in 83 acute myeloid leukemia patients as compared with controls using quantitative real-time polymerase chain reaction (qRT-PCR). Mean gravin expression was 0.53 ± 1.34 and 8.81 ± 11.6 for patients and controls, respectively, and was found to be about 16-fold lower than controls. Gravin gene expression was lower than controls in 83.1 % (69/83) and was similar to controls in 16.9 % (14/83) of cases (p < 0.0001). It was found that there was no significant correlation between gravin expression and laboratory prognostic markers (p > 0.05). Gravin expression was highest in complete remission (1.065 ± 1.79) and lowest in relapse (0.019 ± 0.03) with a statistical difference (p = 0.004). Patients with gravin expression below median level had higher risk to develop relapse (OR = 8.689, 95 % CI = 2.464-30.638; p < 0.0001). No statistical correlation was reported between gravin expression and survival times (OS, DFS) (p = 0.482, 0.409, respectively), and this was confirmed in multivariate analysis. Gravin gene expression was found to be decreased in acute myeloid leukemia, and the degree of its decreased expression has been found to be correlated with poor prognosis.

Kresse SH, Rydbeck H, Skårn M, et al.
Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma.
PLoS One. 2012; 7(11):e48262 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
BACKGROUND: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies.
PRINCIPAL FINDINGS: The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression) using a recurrence threshold of 6/19 (>30%) cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2'-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes.
CONCLUSIONS: Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between DNA copy number, DNA methylation and mRNA expression in osteosarcomas, contributing to better understanding of osteosarcoma biology.

Hayashi M, Nomoto S, Kanda M, et al.
Identification of the A kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma.
J Surg Oncol. 2012; 105(4):381-6 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a major health problem, and identification of new tumor-related genes is an urgent task.
METHODS: To detect tumor-related genes effectively, we performed double-combination array analysis, which consisted of an expression array and a single nucleotide polymorphism (SNP) array of a single surgical HCC specimen.
RESULTS: Expression array analysis identified AKAP12 as one of the genes with reduced expression in HCC tissues when compared with non-cancerous adjacent hepatic tissues. In addition, AKAP12 expression levels in tumor tissues from 48 HCC samples were significantly lower (P < 0.001) than those in normal tissues, and the downregulation was significantly correlated with poor overall survival rate (P = 0.003). However, SNP array analysis revealed that locus 6q24-q25 where AKAP12 was located did not show chromosomal deletion. In contrast, hypermethylation in the AKAP12 promoter regions was observed in 41 of 48 HCC samples. We then confirmed that AKAP12 gene re-expression occurs after 5-aza-2'-deoxycytidine (5-aza-dC) treatment through direct sequence analysis of the AKAP12 promoter region in HCC cell lines.
CONCLUSIONS: The current data suggest that AKAP12 is downregulated in cancer tissues through promoter hypermethylation, and may have a role as a candidate tumor suppressor gene for HCC.

Liu W, Guan M, Hu T, et al.
Re-expression of AKAP12 inhibits progression and metastasis potential of colorectal carcinoma in vivo and in vitro.
PLoS One. 2011; 6(8):e24015 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
BACKGROUND: AKAP12/Gravin (A kinase anchor protein 12) is one of the A-kinase scaffold proteins and a potential tumor suppressor gene in human primary cancers. Our recent study demonstrated the highly recurrent loss of AKAP12 in colorectal cancer and AKAP12 reexpression inhibited proliferation and anchorage-independent growth in colorectal cancer cells, implicating AKAP12 in colorectal cancer pathogenesis.
METHODS: To evaluate the effect of this gene on the progression and metastasis of colorectal cancer, we examined the impact of overexpressing AKAP12 in the AKAP12-negative human colorectal cancer cell line LoVo, the single clone (LoVo-AKAP12) compared to mock-transfected cells (LoVo-CON).
RESULTS: pCMV6-AKAP12-mediated AKAP12 re-expression induced apoptosis (3% to 12.7%, p<0.01), migration (89.6±7.5 cells to 31.0±4.1 cells, p<0.01) and invasion (82.7±5.2 cells to 24.7±3.3 cells, p<0.01) of LoVo cells in vitro compared to control cells. Nude mice injected with LoVo-AKAP12 cells had both significantly reduced tumor volume (p<0.01) and increased apoptosis compared to mice given AKAP12-CON. The quantitative human-specific Alu PCR analysis showed overexpression of AKAP12 suppressed the number of intravasated cells in vivo (p<0.01).
CONCLUSION: These results demonstrate that AKAP12 may play an important role in tumor growth suppression and the survival of human colorectal cancer.

Kim DH, Lee ST, Won HH, et al.
A genome-wide association study identifies novel loci associated with susceptibility to chronic myeloid leukemia.
Blood. 2011; 117(25):6906-11 [PubMed] Related Publications
In the current study, we identified 2 genetic markers for susceptibility to chronic myeloid leukemia (CML) using a genome-wide analysis. A total of 2744 subjects (671 cases and 2073 controls) were included, with 202 Korean CML patients and 497 control subjects enrolled as a discovery set. Significant findings in the discovery set were validated in a second Korean set of 237 patients and 1000 control subjects and in an additional Canadian cohort of European descent, including 232 patients and 576 control subjects. Analysis revealed significant associations of 2 candidate loci, 6q25.1 and 17p11.1, with CML susceptibility, with the lowest combined P values of 2.4 × 10⁻⁶ and 1.3 × 10⁻¹², respectively. Candidate genes in those regions include RMND1, AKAP12, ZBTB2, and WSB1. The locus 6q25.1 was validated in both Korean and European cohorts, whereas 17p11.1 was validated only in the Korean cohort. These findings suggest that genetic variants of 6q25.1 and 17p11.1 may predispose one to the development of CML.

Lee SW, Jung KH, Jeong CH, et al.
Inhibition of endothelial cell migration through the down‑regulation of MMP-9 by A-kinase anchoring protein 12.
Mol Med Rep. 2011 Jan-Feb; 4(1):145-9 [PubMed] Related Publications
Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix (ECM) molecules. ECM degradation is associated with tumor metastasis and angiogenesis. Therefore, the regulation of MMPs is of potential benefit in the treatment of various diseases, including cancer. A-kinase anchoring protein 12 (AKAP12) has been identified as a potential tumor suppressor. However, the function of AKAP12 as a tumor suppressor is not well understood. Herein, to determine the relationship between AKAP12 and MMP-9 in cancer, we first investigated the expression of MMP-9 under normoxic and hypoxic conditions in human fibrosarcoma cells. The expression of MMP-9 was not detected under normoxic conditions.; however, it was markedly increased under hypoxia in HT1080 cells. The effect of AKAP12 on the expression of MMP-9 was subsequently investigated. Hypoxia-induced MMP-9 mRNA expression was significantly reduced by overexpression of AKAP12, as was MMP-9 protein expression. In addition, when the AKAP12 transfectant-conditioned media (CM) were transferred into human endothelial cells, cell migration was significantly inhibited compared to the control group. Notably, the inhibition of AKAP12 expression by siRNA targeting AKAP12 resulted in an increase in the expression of active MMP-2 under normoxia, as well as of MMP-9. Endothelial cell migration was also strongly increased by treatment with CM of siRNA against AKAP12, as compared to the control group. Taken together, the results indicate that AKAP12 is involved in the regulation of endothelial cell migration through the inhibitory regulation of MMP-9 expression in tumor cells.

Liu W, Gong J, Hu J, et al.
Quantitative assessment of AKAP12 promoter methylation in human prostate cancer using methylation-sensitive high-resolution melting: correlation with Gleason score.
Urology. 2011; 77(4):1006.e1-7 [PubMed] Related Publications
OBJECTIVES: To quantitatively investigate the A kinase anchoring protein 12 (AKAP12) gene promoter methylation and its association with clinicopathologic variables in human prostate cancer (PCa). The AKAP12 gene has shown reduced expression and marked hypermethylation in a variety of cancers.
METHODS: The percentage levels of DNA methylation were measured in 78 PCa, 22 benign prostatic hyperplasia, and 22 normal adjacent tissue samples using an AKAP12 methylation-sensitive high-resolution melting assay. AKAP12 gene expression was also examined in 4 human prostate carcinoma cell lines, PC-3, DU145, LNCaP, and 22RV1, using quantitative reverse transcriptase-polymerase chain reaction and methylation-sensitive high-resolution melting analysis and after DNA methyltransferase inhibition with 5-aza-2'-deoxycytidine.
RESULTS: Methylation (>1%) of the AKAP12 promoter region was present in 47 (60.2%) of the 78 PCa, 5 (22.7%) of the 22 benign prostatic hyperplasia, and 2 (9.1%) of the 22 adjacent normal tissue samples. AKAP12 methylation was significantly greater in the PCa than in the benign prostatic hyperplasia or adjacent tissue samples (P < .01). AKAP12 methylation was significantly greater in the PCa samples with higher Gleason scores (P = .03); however, no correlation was found with age, pT category, or serum prostate-specific antigen level. Reverse transcriptase-polymerase chain reaction demonstrated that PC-3 and DU-145 cells expressed AKAP12 RNA and LNCaP and 22RV1 did not. The AKAP12 locus was methylated in the LNCaP and 22RV1 cells. Treatment of LNCaP cells with 5-aza-2'-deoxycytidine markedly decreased the methylation levels and increased the expression of AKAP12.
CONCLUSIONS: The results of the present study have demonstrated that AKAP12 promoter methylation is a frequent event in human PCa. AKAP12 methylation represents a potential molecular biomarker for predicting the malignancy of PCa.

Wu W, Zhang J, Yang H, et al.
Examination of AKAP12 promoter methylation in skin cancer using methylation-sensitive high-resolution melting analysis.
Clin Exp Dermatol. 2011; 36(4):381-5 [PubMed] Related Publications
BACKGROUND: A kinase anchor protein 12 (AKAP12/gravin) belongs to a family of scaffold proteins and organizes protein kinase (PK)A and PKC. DNA hypermethylation in the AKAP12 promoter region has been reported in a variety of human cancers with the exception of skin cancer. Methylation-specific high-resolution melting (MS-HRM) analysis is a novel tool for analysis of promoter methylation.
AIM: To use MS-HRM analysis to detect the methylation levels of the AKAP12 gene in skin samples.
METHODS: In total, 195 samples, including basal cell carcinoma, squamous cell carcinoma and actinic keratosis were examined. MS-HRM analysis was used to detect methylation levels of the AKAP12 gene in these samples.
RESULTS: MS-HRM analysis successfully detected the methylation of AKAP12 in skin samples. The frequencies of AKAP12 methylation in all three types of skin abnormalities were significantly higher than in normal tissues.
CONCLUSIONS: Application of MS-HRM analysis proved to be a fast and high-throughput method to investigate the epigenetic status of AKAP12. Methylation of AKAP12 can be detected in different skin abnormalities.

Jo UH, Whang YM, Sung JS, Kim YH
Methylation of AKAP12{alpha} promoter in lung cancer.
Anticancer Res. 2010; 30(11):4595-600 [PubMed] Related Publications
AKAP12α plays an important role in tumour growth suppression by inducing apoptosis. This study investigated whether the promoter methylation of AKAP12α is associated with lung cancer. AKAP12α was down-regulated in lung cancer cells and the reduced protein expression was restored by DNA methyl-transferase inhibitor. AKAP12α promoter was more frequently methylated in tumours than in normal tissues. Furthermore, AKAP12α methylation was found more frequently in the cells of non-relapse patients after surgery than in those of early relapse patients. In conclusion, this study demonstrated that AKAP12α expression is regulated by DNA methylation and that AKAP12α promoter methylation is associated with lung cancer prognosis.

Delidaki M, Gu M, Hein A, et al.
Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line.
Mol Cell Endocrinol. 2011; 332(1-2):213-20 [PubMed] Related Publications
Differentiation of human placental mononuclear trophoblasts into a multinucleate syncytium involves up-regulation of key proteins promoting cell fusion and increased capacity for placental hormonogenesis. It is well established that the activation of adenylyl cyclase leads to increased expression of trophoblast fusogenic gene machinery and human chorionic gonadotropin (hCG) secretion. We used the forskolin-induced syncytialisation of BeWo choriocarcinoma cells as a model to characterise in detail the signalling pathway downstream of adenylyl cyclase. Forskolin treatment induced a rapid and potent ERK1/2 and p38MAPK phosphorylation; this cascade required PKA-AKAP interactions and led to downstream CREB-1/ATF-1 phosphorylation via ERK1/2-dependent but p38MAPK-independent mechanisms. Interestingly both p38MAPK and ERK1/2 were involved in forskolin-induced hCG-secretion, suggesting the presence of additional p38MAPK-dependent but CREB-1/ATF-1-independent pathways. Forskolin treatment of BeWo cells significantly up-regulated the expression of various fusogenic gene mRNAs, including syncytin-1 and -2 (by 3- and 10-fold, respectively) the transcription factors old astrocyte specifically induced substance (OASIS) and glial cells missing a (GCMa) (by 3- and 6-fold, respectively) and the syncytin-2 receptor, major facilitator superfamily domain containing 2 (MFSD2) (by 2-fold). Up-regulation of AKAP79 and AKAP250 (by 2.5- and 4-fold, respectively) was also identified in forskolin-treated BeWo cells. Forskolin effects on all these genes were suppressed by chemical inhibition of p38MAPK whereas only specific genes were sensitive to ERK1/2 inhibition. This data provide novel insights into the signalling molecules and mechanisms regulating fusogenic gene expression by the adenylyl cyclase pathway.

Goeppert B, Schmezer P, Dutruel C, et al.
Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms.
Hepatology. 2010; 52(6):2023-33 [PubMed] Related Publications
UNLABELLED: The A kinase anchor protein 12 (AKAP12) is a central mediator of protein kinase A and protein kinase C signaling. Although AKAP12 has been described to act as a tumor suppressor and its expression is frequently down-regulated in several human malignancies, the underlying molecular mechanisms responsible for the AKAP12 reduction are poorly understood. We therefore analyzed the expression of AKAP12 and its genetic and epigenetic regulatory mechanisms in human hepatocarcinogenesis. Based on tissue microarray analyses (n = 388) and western immunoblotting, we observed a significant reduction of AKAP12 in cirrhotic liver (CL), premalignant lesions (DN), and hepatocellular carcinomas (HCCs) compared to histologically normal liver specimens (NL). Analyses of array comparative genomic hybridization data (aCGH) from human HCCs revealed chromosomal losses of AKAP12 in 36% of cases but suggested additional mechanisms underlying the observed reduction of AKAP12 expression in hepatocarcinogenesis. Quantitative methylation analysis by MassARRAY of NL, CL, DN, and HCC tissues, as well as of various tumorigenic and nontumorigenic liver cell lines revealed specific hypermethylation of the AKAP12α promoter but not of the AKAP12β promoter in HCC specimens and in HCC cell lines. Consequently, restoration experiments performed with 5-aza-2'deoxycytidine drastically increased AKAP12α mRNA levels in a HCC cell line (AKN1) paralleled by AKAP12α promoter demethylation. As hypermethylation is not observed in CL and DN, we investigated microRNA-mediated posttranscriptional regulation as an additional mechanism to explain reduced AKAP12 expression. We found that miR-183 and miR-186 are up-regulated in CL and DN and are able to target AKAP12.
CONCLUSION: In addition to genetic alterations, epigenetic mechanisms are responsible for the reduction of the tumor suppressor gene AKAP12 in human hepatocarcinogenesis.

Mardin WA, Petrov KO, Enns A, et al.
SERPINB5 and AKAP12 - expression and promoter methylation of metastasis suppressor genes in pancreatic ductal adenocarcinoma.
BMC Cancer. 2010; 10:549 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
BACKGROUND: Early metastasis and infiltration are survival limiting characteristics of pancreatic ductal adenocarcinoma (PDAC). Thus, PDAC is likely to harbor alterations in metastasis suppressor genes that may provide novel diagnostic and therapeutic opportunities. This study investigates a panel of metastasis suppressor genes in correlation to PDAC phenotype and examines promoter methylation for regulatory influence on metastasis suppressor gene expression and for its potential as a diagnostic tool.
METHODS: Metastatic and invasive potential of 16 PDAC cell lines were quantified in an orthotopic mouse model and mRNA expression of 11 metastasis suppressor genes determined by quantitative RT-PCR. Analysis for promoter methylation was performed using methylation specific PCR and bisulfite sequencing PCR. Protein expression was determined by Western blot.
RESULTS: In general, higher metastasis suppressor gene mRNA expression was not consistent with less aggressive phenotypes of PDAC. Instead, mRNA overexpression of several metastasis suppressor genes was found in PDAC cell lines vs. normal pancreatic RNA. Of the investigated metastasis suppressor genes, only higher AKAP12 mRNA expression was correlated with decreased metastasis (P < 0.05) and invasion scores (P < 0.01) while higher SERPINB5 mRNA expression was correlated with increased metastasis scores (P < 0.05). Both genes' promoters showed methylation, but only increased SERPINB5 methylation was associated with loss of mRNA and protein expression (P < 0.05). SERPINB5 methylation was also directly correlated to decreased metastasis scores (P < 0.05).
CONCLUSIONS: AKAP12 mRNA expression was correlated to attenuated invasive and metastatic potential and may be associated with less aggressive phenotypes of PDAC while no such evidence was obtained for the remaining metastasis suppressor genes. Increased SERPINB5 mRNA expression was correlated to increased metastasis and mRNA expression was regulated by methylation. Thus, SERPINB5 methylation was directly correlated to metastasis scores and may provide a diagnostic tool for PDAC.

Liu W, Guan M, Su B, et al.
Quantitative assessment of AKAP12 promoter methylation in colorectal cancer using methylation-sensitive high resolution melting: Correlation with Duke's stage.
Cancer Biol Ther. 2010; 9(11):862-71 [PubMed] Related Publications
BACKGROUND: The expression of AKAP12 (A Kinase anchoring protein 12) is markedly reduced in a variety of cancers. The purpose of this study was to establish a methylation-sensitive high resolution melting (MS-HRM) assay for the quantitative detection of AKAP12 promoter methylation and expression and the association with clinicopathological variables in human colorectal cancer. We also assessed the effect of AKAP12 re-expression on cell growth and colony formation.
RESULTS: Downregulation or loss of AKAP12 mRNA expression was detected in 31 of 45 tissue samples (68.9%). No significant correlation was observed between the reduced expression levels and patient age, gender, Duke's stage or tumor differentiation. Methylation (>1%) of the AKAP12 promoter region was present in 35 of 45 (77.8%) carcinoma tissue samples and 6 of 45 (13.3%) adjacent tissue samples. AKAP12 methylation was significantly higher in the colorectal cancer tissues exhibiting advanced Duke's stages. Treatment of the three colorectal carcinoma cell lines (LoVo, COLO320 and SW480) with completely methylated AKAP12 with inhibitors of DNA methyltransferase (5-Aza-2'-deoxycytidine) markedly increased expression of AKAP12 and decreased methylation levels. Ectopic expression of AKAP12 in the LoVo cell line suppressed cell growth and inhibited colony formation.
METHODS: The AKAP12 gene was examined by quantitative RT-PCR, MS-HRM analysis and bisulfite sequencing in 45 paired tissue samples obtained from primary colorectal carcinomas and the corresponding adjacent tissues. In addition, five colorectal carcinoma cell lines (LoVo, COLO205, SW480, LS174T and COLO320) were investigated and western blot analysis was used to investigate changes in protein expression. A proliferation assay and soft agar assay were performed after overexpression of AKAP12.
CONCLUSION: Our study demonstrated that MS-HRM is a robust, fast and sensitive method for AKAP12 methylation analysis. AKAP12 methylation represents a potential molecular biomarker for predicting the malignancy of this cancer.

Liu W, Guan M, Su B, et al.
Rapid determination of AKAP12 promoter methylation levels in peripheral blood using methylation-sensitive high resolution melting (MS-HRM) analysis: application in colorectal cancer.
Clin Chim Acta. 2010; 411(13-14):940-6 [PubMed] Related Publications
BACKGROUND: Colorectal cancer is the third most common form of cancer and hypermethylation has been shown to increase the risk of developing this disease. DNA hypermethylation in the A kinase anchor protein 12 (AKAP12/Gravin) promoter region and the accompanied underexpression of it has been noted in a variety of human cancers.
METHODS: We applied methylation-specific high resolution melting (MS-HRM) technology to detect quantitatively A kinase anchor protein 12 (AKAP12/Gravin) methylation in peripheral blood from 100 colorectal cancer patients and 50 healthy volunteers and in 3 colorectal cancer cell lines.
RESULTS: In this study 48 of the 100 colorectal cancer samples (48%) were found to be methylated at the AKAP12 promoter region. AKAP12 methylation was significantly higher in the colorectal cancer samples with differentiation (p=0.03). We also compared the results generated by MS-HRM with a traditional methylation-specific PCR (MSP) assay. We found that intra-assay variability ranged from 6.14 to 9.90% and inter-assay variability ranged from 14.5 to 17.2%. The AKAP12 MS-HRM assay was able to reproducibly detect 1% methylated DNA, whereas the MSP method was unable to detect less than 5% methylation.
CONCLUSIONS: We demonstrate the utility of quantitative AKAP12 MS-HRM analysis of promoter methylation in peripheral blood samples. AKAP12 MS-HRM quantitative methods with excellent detection capabilities have many promising applications in the research and diagnosis of colorectal cancer.

Su B, Bu Y, Engelberg D, Gelman IH
SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway.
J Biol Chem. 2010; 285(7):4578-86 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
SSeCKS/Gravin/AKAP12 ("SSeCKS") encodes a cytoskeletal protein that regulates G(1) --> S progression by scaffolding cyclins, protein kinase C (PKC) and PKA. SSeCKS is down-regulated in many tumor types including prostate, and when re-expressed in MAT-LyLu (MLL) prostate cancer cells, SSeCKS selectively inhibits metastasis by suppressing neovascularization at distal sites, correlating with its ability to down-regulate proangiogenic genes including Vegfa. However, the forced re-expression of VEGF only rescues partial lung metastasis formation. Here, we show that SSeCKS potently inhibits chemotaxis and Matrigel invasion, motility parameters contributing to metastasis formation. SSeCKS suppressed serum-induced activation of the Raf/MEK/ERK pathway, resulting in down-regulation of matrix metalloproteinase-2 expression. In contrast, SSeCKS had no effect on serum-induced phosphorylation of the Src substrate, Shc, in agreement with our previous data that SSeCKS does not inhibit Src kinase activity in cells. Invasiveness and chemotaxis could be restored by the forced expression of constitutively active MEK1, MEK2, ERK1, or PKCalpha. SSeCKS suppressed phorbol ester-induced ERK1/2 activity only if it encoded its PKC binding domain (amino acids 553-900), suggesting that SSeCKS attenuates ERK activation through a direct scaffolding of conventional and/or novel PKC isozymes. Finally, control of MLL invasiveness by SSeCKS is influenced by the actin cytoskeleton: the ability of SSeCKS to inhibit podosome formation is unaffected by cytochalasin D or jasplakinolide, whereas its ability to inhibit MEK1/2 and ERK1/2 activation is nullified by jasplakinolide. Our findings suggest that SSeCKS suppresses metastatic motility by disengaging activated Src and then inhibiting the PKC-Raf/MEK/ERK pathways controlling matrix metalloproteinase-2 expression and podosome formation.

Tessema M, Belinsky SA
Mining the epigenome for methylated genes in lung cancer.
Proc Am Thorac Soc. 2008; 5(8):806-10 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
Lung cancer has become a global public health burden, further substantiating the need for early diagnosis and more effective targeted therapies. The key to accomplishing both these goals is a better understanding of the genes and pathways disrupted during the initiation and progression of this disease. Gene promoter hypermethylation is an epigenetic modification of DNA at promoter CpG islands that together with changes in histone structure culminates in loss of transcription. The fact that gene promoter hypermethylation is a major mechanism for silencing genes in lung cancer has stimulated the development of screening approaches to identify additional genes and pathways that are disrupted within the epigenome. Some of these approaches include restriction landmark scanning, methylation CpG island amplification coupled with representational difference analysis, and transcriptome-wide screening. Genes identified by these approaches, their function, and prevalence in lung cancer are described. Recently, we used global screening approaches to interrogate 43 genes in and around the candidate lung cancer susceptibility locus, 6q23-25. Five genes, TCF21, SYNE1, AKAP12, IL20RA, and ACAT2, were methylated at 14 to 81% prevalence, but methylation was not associated with age at diagnosis or stage of lung cancer. These candidate tumor suppressor genes likely play key roles in contributing to sporadic lung cancer. The realization that methylation is a dominant mechanism in lung cancer etiology and its reversibility by pharmacologic agents has led to the initiation of translational studies to develop biomarkers in sputum for early detection and the testing of demethylating and histone deacetylation inhibitors for treatment of lung cancer.

Bonazzi VF, Irwin D, Hayward NK
Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma.
Genes Chromosomes Cancer. 2009; 48(1):10-21 [PubMed] Related Publications
Tumor suppressor genes (TSGs) are sometimes inactivated by transcriptional silencing through promoter hypermethylation. To identify novel methylated TSGs in melanoma, we carried out global mRNA expression profiling on a panel of 12 melanoma cell lines treated with a combination of 5-Aza-2-deoxycytidine (5AzadC) and an inhibitor of histone deacetylase, Trichostatin A. Reactivation of gene expression after drug treatment was assessed using Illumina whole-genome microarrays. After qRT-PCR confirmation, we followed up 8 genes (AKAP12, ARHGEF16, ARHGAP27, ENC1, PPP1R3C, PPP1R14C, RARRES1, and TP53INP1) by quantitative DNA methylation analysis using mass spectrometry of base-specific cleaved amplification products in panels of melanoma cell lines and fresh tumors. PPP1R3C, ENC1, RARRES1, and TP53INP1, showed reduced mRNA expression in 35-59% of the melanoma cell lines compared to melanocytes and which was correlated with a high proportion of promoter methylation (>40-60%). The same genes also showed extensive promoter methylation in 6-25% of the tumor samples, thus confirming them as novel candidate TSGs in melanoma.

Hacker E, Muller K, Whiteman DC, et al.
Reduced expression of IL-18 is a marker of ultraviolet radiation-induced melanomas.
Int J Cancer. 2008; 123(1):227-31 [PubMed] Related Publications
We previously showed that mice carrying an activated Cdk4 mutation together with melanocyte-specific mutant Hras (Cdk4(R24C/R24C)/TPras) develop melanoma spontaneously, but penetrance is increased and age of onset reduced after neonatal ultraviolet radiation (UVR) exposure. UVR-treated mice were more likely to develop multiple primary lesions, and these melanomas more often expressed Trp53, and less often expressed c-Myc, than melanomas from nonirradiated mice (Hacker et al., Cancer Res 2006;66:2946-52). These data suggest differences in mechanisms of tumorigenesis between melanomas developing spontaneously, or as a result of UVR exposure. To further delineate these differences, we compared global gene expression between spontaneous and UVR-induced melanomas from these mice using microarrays. We found 264 genes differentially expressed between these groups (ANOVA, p < 0.05). Selected candidate genes were validated using qRT-PCR, which confirmed upregulation of Gpr155 and Bmp7, and downregulation of Plagl1, Akap12 and Il18 in UVR-induced mouse melanomas. In humans, epidemiological studies suggest that there may be 2 predominant pathways to melanoma development. One characterized by chronic UVR exposure and which leads mainly to melanomas on sun-exposed sites; the other associated with low UVR exposure and leading predominantly to melanomas on less-exposed body sites. We found by immunohistochemical analysis that, comparing a series of human melanomas from the head (a chronically sun-exposed site; N = 82) with a set from the trunk (an intermittently exposed site; N = 65), the prevalence of IL-18 expression was significantly lower in melanomas on the head (16%) than on truncal melanomas (34%, p = 0.011). We conclude that loss of IL-18 is a marker of UVR-induced melanoma, both in animal models and humans.

Tessema M, Willink R, Do K, et al.
Promoter methylation of genes in and around the candidate lung cancer susceptibility locus 6q23-25.
Cancer Res. 2008; 68(6):1707-14 [PubMed] Related Publications
Chromosomal aberrations associated with lung cancer are frequently observed in the long arm of chromosome 6. A candidate susceptibility locus at 6q23-25 for lung cancer was recently identified; however, no tumor suppressor genes inactivated by mutation have been identified in this locus. Genetic, epigenetic, gene expression, and in silico screening approaches were used to select 43 genes located in 6q12-27 for characterization of methylation status. Twelve (28%) genes were methylated in at least one lung cancer cell line, and methylation of 8 genes was specific to lung cancer cell lines. Five of the 8 genes with the highest prevalence for methylation in cell lines (TCF21, SYNE1, AKAP12, IL20RA, and ACAT2) were examined in primary lung adenocarcinoma samples from smokers (n = 100) and never smokers (n = 75). The prevalence for methylation of these genes was 81%, 50%, 39%, 26%, and 14%, respectively, and did not differ by smoking status or age at diagnosis. Transcription of SYNE1, AKAP12, and IL20RA was completely silenced by hypermethylation and could be restored after treatment with 5-aza-2-deoxycytidine. Significant associations were found between methylation of SYNE1 and TCF21, SYNE1 and AKAP12, and AKAP12 and IL20RA, indicating a coordinated inactivation of these genes in tumors. A higher prevalence for methylation of these genes was not associated with early-onset lung cancer cases, most likely precluding their involvement in familial susceptibility to this disease. Together, our results indicate that frequent inactivation of multiple candidate tumor suppressor genes within chromosome 6q likely contributes to development of sporadic lung cancer.

Jin Z, Hamilton JP, Yang J, et al.
Hypermethylation of the AKAP12 promoter is a biomarker of Barrett's-associated esophageal neoplastic progression.
Cancer Epidemiol Biomarkers Prev. 2008; 17(1):111-7 [PubMed] Related Publications
The A-kinase anchoring protein 12 (AKAP12) is a kinase scaffold protein with known tumor suppressor activity. Recently, AKAP12 promoter hypermethylation was reported in gastric and colorectal cancers. We examined AKAP12 promoter hypermethylation using real-time methylation-specific PCR in 259 human esophageal tissues. AKAP12 hypermethylation showed highly discriminative receiver-operator characteristic (ROC) curve profiles, clearly distinguishing esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma and normal esophagus (P < 0.0001). AKAP12-normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's, and EAC than in normal esophagus (P < 0.0000001). AKAP12 hypermethylation frequency was zero in normal esophagus but increased early during neoplastic progression, to 38.9% in BE from patients with Barrett's alone, 52.5% in dysplastic Barrett's metaplasia, and 52.2% in EAC. AKAP12 hypermethylation levels were significantly higher in normal esophageal epithelia from patients with EAC (mean = 0.00082) than in normal esophagi from patients without Barrett's or esophageal cancer (mean = 0.00007; P = 0.006). There was a significant correlation between AKAP12 hypermethylation and BE segment length, a known clinical neoplastic progression risk factor. In contrast, only 2 (7.7%) of 26 esophageal squamous cell carcinomas exhibited AKAP12 hypermethylation. Treatment of BIC and OE33 EAC cells with 5-aza-2'-deoxycytidine reduced AKAP12 methylation and increased AKAP12 mRNA expression. AKAP12 mRNA levels in EACs with unmethylated AKAP12 (mean = 0.1663) were higher than in EACs with methylated AKAP12 (mean = 0.0668). We conclude that promoter hypermethylation of AKAP12 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker for the early detection of EAC.

Heller G, Schmidt WM, Ziegler B, et al.
Genome-wide transcriptional response to 5-aza-2'-deoxycytidine and trichostatin a in multiple myeloma cells.
Cancer Res. 2008; 68(1):44-54 [PubMed] Related Publications
To identify epigenetically silenced cancer-related genes and to determine molecular effects of 5-aza-2'-deoxycytidine (Aza-dC) and/or trichostatin A (TSA) in multiple myeloma (MM), we analyzed global changes in gene expression profiles of three MM cell lines by microarray analysis. We identified up-regulation of several genes whose epigenetic silencing in MM is well known. However, much more importantly, we identified a large number of epigenetically inactivated cancer-related genes that are involved in various physiologic processes and whose epigenetic regulation in MM was unknown thus far. In addition, drug treatment of MM cell lines resulted in down-regulation of several MM proliferation-associated factors (i.e., MAF, CCND1/2, MYC, FGFR3, MMSET). Ten Aza-dC and/or TSA up-regulated genes (CPEB1, CD9, GJA1, BCL7c, GADD45G, AKAP12, TFPI2, CCNA1, SPARC, and BNIP3) were selected for methylation analysis in six MM cell lines, 24 samples from patients with monoclonal gammopathy of undetermined significance (MGUS), and 111 samples from patients with MM. Methylation frequencies of these genes ranged between 0% and 17% in MGUS samples and between 5% and 50% in MM samples. Interestingly, methylation of SPARC and BNIP3 was statistically significantly associated with a poor overall survival of MM patients (P = 0.003 and P = 0.017, respectively). Moreover, SPARC methylation was associated with loss of SPARC protein expression by immunostaining in a subset of MM patients. In conclusion, we identified new targets for aberrant methylation in monoclonal gammopathies, and our results suggest that DNA methyltransferase and histone deacetylase inhibition might play an important role in the future treatment of patients with MM.

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