Gene Summary

Gene:KAT5; K(lysine) acetyltransferase 5
Summary:The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:histone acetyltransferase KAT5
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (25)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 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.

  • Lysine
  • Western Blotting
  • Acetyltransferases
  • beta Catenin
  • Chromosome 11
  • Histone Acetyltransferases
  • Nuclear Proteins
  • Neoplastic Cell Transformation
  • Messenger RNA
  • X-Linked Inhibitor of Apoptosis Protein
  • Transcriptional Activation
  • Androgen Receptors
  • Gene Expression Profiling
  • Promoter Regions
  • Protein Processing, Post-Translational
  • Tumor Markers
  • Immunohistochemistry
  • KAT5
  • Histones
  • Proto-Oncogene Proteins
  • DNA-Binding Proteins
  • Up-Regulation
  • Trans-Activators
  • Cultured Cells
  • Cell Proliferation
  • Neoplasm Invasiveness
  • Flow Cytometry
  • Prostate Cancer
  • Down-Regulation
  • Cancer Gene Expression Regulation
  • Oligonucleotide Array Sequence Analysis
  • DNA Damage
  • Neoplasm Proteins
  • Bladder Cancer
  • Apoptosis
  • Transcription
  • Thyroid Cancer
  • Thyrotropin
  • Acetylation
  • Transfection
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: KAT5 (cancer-related)

Zhang J, Liu H, Pan H, et al.
The histone acetyltransferase hMOF suppresses hepatocellular carcinoma growth.
Biochem Biophys Res Commun. 2014; 452(3):575-80 [PubMed] Related Publications
Males absent on the first (MOF) is a histone acetyltransferase belongs to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. In mammals, MOF plays critical roles in transcription activation by acetylating histone H4K16, a prevalent mark associated with chromatin decondensation. MOF can also acetylate transcription factor p53 on K120, which is important for activation of pro-apoptotic genes; and TIP5, the largest subunit of NoRC, on K633. However, the role of hMOF in hepatocellular carcinoma remains unknown. Here we find that the expression of hMOF is significantly down-regulated in human hepatocellular carcinoma and cell lines. Furthermore, our survival analysis indicates that low hMOF expression predicts poor overall and disease-free survival. We demonstrate that hMOF knockdown promotes hepatocellular carcinoma growth in vitro and in vivo, while hMOF overexpression reduces hepatocellular carcinoma growth in vitro and in vivo. Mechanically, we show that hMOF regulates the expression of SIRT6 and its downstream genes. In summary, our findings demonstrate that hMOF participates in human hepatocellular carcinoma by targeting SIRT6, and hMOF activators may serve as potential drug candidates for hepatocellular carcinoma therapy.

Lee SH, Lee S, Yang H, et al.
Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.
Circ Res. 2014; 115(2):215-26 [PubMed] Related Publications
RATIONALE: The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown.
OBJECTIVE: To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis.
METHODS AND RESULTS: Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis.
CONCLUSIONS: Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.

Jaganathan A, Chaurasia P, Xiao GQ, et al.
Coactivator MYST1 regulates nuclear factor-κB and androgen receptor functions during proliferation of prostate cancer cells.
Mol Endocrinol. 2014; 28(6):872-85 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
In prostate cancer (PCa), the functional synergy between androgen receptor (AR) and nuclear factor-κ B (NF-κB) escalates the resistance to therapeutic regimens and promotes aggressive tumor growth. Although the underlying mechanisms are less clear, gene regulatory abilities of coactivators can bridge the transcription functions of AR and NF-κB. The present study shows that MYST1 (MOZ, YBF2 and SAS2, and TIP60 protein 1) costimulates AR and NF-κB functions in PCa cells. We demonstrate that activation of NF-κB promotes deacetylation of MYST1 by sirtuin 1. Further, the mutually exclusive interactions of MYST1 with sirtuin 1 vs AR regulate the acetylation of lysine 16 on histone H4. Notably, in AR-lacking PC3 cells and in AR-depleted LNCaP cells, diminution of MYST1 activates the cleavage of poly(ADP-ribose) polymerase and caspase 3 that leads to apoptosis. In contrast, in AR-transformed PC3 cells (PC3-AR), depletion of MYST1 induces cyclin-dependent kinase (CDK) N1A/p21, which results in G2M arrest. Concomitantly, the levels of phospho-retinoblastoma, E2F1, CDK4, and CDK6 are reduced. Finally, the expression of tumor protein D52 (TPD52) was unequivocally affected in PC3, PC3-AR, and LNCaP cells. Taken together, the results of this study reveal that the functional interactions of MYST1 with AR and NF-κB are critical for PCa progression.

Shi J, Wang Y, Zeng L, et al.
Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.
Cancer Cell. 2014; 25(2):210-25 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we report a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a "histone H4-mimic" GK-X-GK motif that is diacetylated by Tip60. The diacetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.

Zhu C, Sun Z, Li C, et al.
Urocortin affects migration of hepatic cancer cell lines via differential regulation of cPLA2 and iPLA2.
Cell Signal. 2014; 26(5):1125-34 [PubMed] Related Publications
Urocortin (UCN) is a member of corticotrophin-releasing factor (CRF) family, which has been reported to play a role in many biological processes, including inflammation and cancer development. Growing evidence shows that PLA2 (phospholipase A2) enzymes also participate in inflammation and tumor development. The primary aim of the present study was to identify a novel signaling pathway of CRF receptor activation leading to migration of two kinds of hepatoma carcinoma cell lines, HepG2 and SMMC-7721, linking the stimulation of PLA2 expression by UCN to UCN-induced tumor cell migration. Pharmacological inhibitors and genetic approaches (such as stable transfection and siRNAs) were used in this study. Unlike HepG2 cells which express both CRF receptors themselves, SMMC-7721 cells which hardly express these two CRF receptors needed stable transfection with CRFR1 or CRFR2 to observe the effect of UCN. Two types of PLA2 enzymes, cPLA2 and iPLA2, were found to be regulated by UCN. Our data showed that UCN raised cPLA2 expression but lowered iPLA2 expression. Moreover, UCN was found to act on the certain region of iPLA2 promoter to reduce its transcription. UCN promoted tumor cell migration by up-regulating cPLA2 expression via CRFR1 whereas it suppressed tumor cell migration by down-regulating iPLA2 expression via CRFR2. These results indicate the dual roles for UCN in the hepatoma carcinoma cell migration, which involve the regulation of both cPLA2and iPLA2.

Yun HM, Park KR, Lee HP, et al.
PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities.
Free Radic Biol Med. 2014; 69:367-76 [PubMed] Related Publications
PRDX6 is a bifunctional protein with both glutathione peroxidase (GPx) and calcium-independent phospholipase A2 (iPLA2) activities, which are concomitantly increased with the expression of PRDX6. PRDX6 promoted lung tumor growth in an in vivo allograft model. Herein, we further studied the vital roles in tumor progression of PRDX6 in lung cancer using nude mice bearing PRDX6-overexpressing lung cancer cells. Nude mice xenografted with PRDX6 showed increases in tumor size and weight compared to control mice. Histopathological and Western blotting examination demonstrated that expression of proliferating cell nuclear antigen, vascular endothelial growth factor, metalloproteinases 2 and 9, and cyclin-dependent kinases accompanied by increased iPLA2 and GPx activities were increased in the tumor tissues of PRDX6-overexpressing nude mice. In tumor tissues of PRDX6-overexpressing mice, the activation of mitogen-activated protein kinases and AP-1 DNA binding were also increased. The growth of lung cancer cell lines (A549 and NCI-H460) was enhanced by the increase in iPLA2 and GPx activities of PRDX6. In addition, mutant PRDX6 (C47S) attenuated PRDX6-mediated p38, ERK1/2, and AP-1 activities as well as its enzyme activities in the A549 and NCI-H460 lines. Furthermore, tumor growth and p38, ERK1/2, and AP-1 activities were also inhibited in nude mice bearing mutant PRDX6 (C47S) compared to PRDX6. Therefore, our findings indicate that PRDX6 promotes lung tumor growth via increased glutathione peroxidase and iPLA2 activities.

Arjonen A, Kaukonen R, Mattila E, et al.
Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis.
J Clin Invest. 2014; 124(3):1069-82 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

Yang Y, Han X, Guan J, Li X
Regulation and function of histone acetyltransferase MOF.
Front Med. 2014; 8(1):79-83 [PubMed] Related Publications
The mammalian MOF (male absent on the first), a member of the MYST (MOZ, YBF2, SAS2, and Tip60) family of histone acetyltransferases (HATs), is the major enzyme that catalyzes the acetylation of histone H4 on lysine 16. Acetylation of K16 is a prevalent mark associated with chromatin decondensation. MOF has recently been shown to play an essential role in maintaining normal cell functions. In this study, we discuss the important roles of MOF in DNA damage repair, apoptosis, and tumorigenesis. We also analyze the role of MOF as a key regulator of the core transcriptional network of embryonic stem cells.

Feng FL, Yu Y, Liu C, et al.
KAT5 silencing induces apoptosis of GBC-SD cells through p38MAPK-mediated upregulation of cleaved Casp9.
Int J Clin Exp Pathol. 2014; 7(1):80-91 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
The poor overall prognosis of Gallbladder carcinoma (GBC) patients and the limited therapeutic regimens for these patients demonstrates the need for better therapeutic modalities, while the growing evidences have indicated that those genes contributed to epigenetic regulation may serve as therapeutic targets. The function of histone acetylation on growth and survival of GBC cells remains unknown. In present study, an RNAi screening of 16 genes involving histone acetyltransferases (HATs) was applied to GBC-SD cells and we found that KAT5 knockdown specifically inhibits the proliferation of GBC-SD cells by casp9-mediated apoptosis. Microarray data analysis showed that KAT5 RNAi may result in cleaved casp9 upregulation through p38MAPK activation in GBC-SD cells. The mRNA expression level of KAT5 was significantly upregulated in GBC tissues than in the adjacent normal tissues. In consistence with the mRNA level, the protein expression of KAT5 was markedly increased in tissues from patients with poor prognosis than those with good prognosis. These findings strongly indicated that KAT5 was implicated in GBC tumorigenesis and that its expression level was associated with the prognosis. Our work may also provide a potential therapeutic target for treatment of GBC patients.

Huang CF, Zhang L, Ma SR, et al.
Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma.
PLoS One. 2013; 8(12):e83479 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Oxidative stress has been reported to play an important role in progression and prognostication in various kinds of cancers. However, the role and clinical significance of oxidative stress markers Keap1 and Nrf2 in oral squamous cell carcinoma (OSCC) has not been elucidated. This study aimed to investigate the correlation of oxidative stress markers Keap1 and Nrf2 expression and pathological features in OSCC by using tissue microarray. Tissue microarrays containing 17 normal oral mucosa, 7 oral epithelial dysplasia and 43 OSCC specimens were studied by immunohistochemistry. The association among these proteins and pathological features were analyzed. Expression of oxidative stress markers Keap1, Nrf2, and antioxidants PPIA, Prdx6, as well as CD147 was found to increase consecutively from normal oral mucosa to OSCC, and the Keap1, Nrf2, PPIA, Prdx6, CD147 expression in OSCC were significantly higher when compared to normal oral mucosa. Expression of Keap1, Nrf2 in tumors was not found to be significantly associated with T category, lymph node metastases, and pathological grade. Furthermore, we checked the relationship among these oxidative stress markers and found that Keap1 was significantly correlated with Nrf2, Prdx6 and CD147. Significant relationship between Nrf2 and Prdx6 was also detected. Finally, we found patients with overexpression of Keap1 and Nrf2 had not significantly worse overall survival by Kaplan-Meier analysis. These findings suggest that ROS markers are associated with carcinogenesis and progression of OSCC, which may have prognostic value and could be regarded as potential therapeutic targets in OSCC.

Ferrarini A, Gaillard M, Guerry F, et al.
Potocki-Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype.
Am J Med Genet A. 2014; 164A(2):346-52 [PubMed] Related Publications
Frontonasal dysplasia (FND) is a genetically heterogeneous malformation spectrum with marked hypertelorism, broad nasal tip and bifid nose. Only a small number of genes have been associated with FND phenotypes until now, the first gene being EFNB1, related to craniofrontonasal syndrome (CFNS) with craniosynostosis in addition, and more recently the aristaless-like homeobox genes ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively. We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. While molecular investigations did not reveal mutations in any of the known genes, ALX4, ALX3, ALX1 and EFNB1, comparative genomic hybridization (array CGH) techniques showed a large heterozygous de novo deletion at 11p11.12p12, encompassing the ALX4 gene. Deletions in this region have been described in patients with Potocki-Shaffer syndrome (PSS), characterized by biparietal foramina, multiple exostoses, and intellectual disability. Although the patient reported herein manifests some overlapping features of FND and PPS, it is likely that the observed phenotype maybe due to a second unidentified mutation in the ALX4 gene. The phenotype will be discussed in view of the deleted region encompassing the ALX4 gene.

Cattaneo M, Baronchelli S, Schiffer D, et al.
Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid.
J Biol Chem. 2014; 289(5):2826-38 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Valproic acid (VPA), an histone deacetylase inhibitor, is emerging as a promising therapeutic agent for the treatments of gliomas by virtue of its ability to reactivate the expression of epigenetically silenced genes. VPA induces the unfolded protein response (UPR), an adaptive pathway displaying a dichotomic yin yang characteristic; it initially contributes in safeguarding the malignant cell survival, whereas long-lasting activation favors a proapoptotic response. By triggering UPR, VPA might tip the balance between cellular adaptation and programmed cell death via the deregulation of protein homeostasis and induction of proteotoxicity. Here we aimed to investigate the impact of proteostasis on glioma stem cells (GSC) using VPA treatment combined with subversion of SEL1L, a crucial protein involved in homeostatic pathways, cancer aggressiveness, and stem cell state maintenance. We investigated the global expression of GSC lines untreated and treated with VPA, SEL1L interference, and GSC line response to VPA treatment by analyzing cell viability via MTT assay, neurosphere formation, and endoplasmic reticulum stress/UPR-responsive proteins. Moreover, SEL1L immunohistochemistry was performed on primary glial tumors. The results show that (i) VPA affects GSC lines viability and anchorage-dependent growth by inducing differentiative programs and cell cycle progression, (ii) SEL1L down-modulation synergy enhances VPA cytotoxic effects by influencing GSCs proliferation and self-renewal properties, and (iii) SEL1L expression is indicative of glioma proliferation rate, malignancy, and endoplasmic reticulum stress statuses. Targeting the proteostasis network in association to VPA treatment may provide an alternative approach to deplete GSC and improve glioma treatments.

He W, Zhang MG, Wang XJ, et al.
KAT5 and KAT6B are in positive regulation on cell proliferation of prostate cancer through PI3K-AKT signaling.
Int J Clin Exp Pathol. 2013; 6(12):2864-71 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Histone modifications play important roles in the tumorigenesis and progression of prostate cancer (PCa) and genes involved in histone modifications are seemed as ideal targets for treatment of PCa patients. However, clinical trials have shown that those existing drugs exert the minimal antitumor activity and excess adverse effects on PCa patients. Therefore, it is of great interest to figure out novel specific biomarkers to guide the development of new drugs. In present study, an RNAi screening with 44 genes involved in histone modifications was applied to a PCa cell line, Du145. The results showed that nine genes were in positive regulation of Du145 cell growth. Then four selected genes (KAT2B, KAT5, KAT6B and HDAC1) were found to exert this effect by a gene-specific manner when silenced. And then KAT5 or KAT6B silenced cells were subjected to DNA microarray analysis. The common differentially expressed genes were analyzed by Ingenuity Pathway Analysis (IPA) and found that PDEF signaling, EIF2 signaling and PI3K signaling was suppressed following by KAT5 or KAT6B silencing. Subsequent immunoblotting assay showed that AKT signaling was inhibited, which suggested that KAT5 or KAT6B regulates cancer cell growth through PI3K-AKT signaling. Together with our published data [31] that AURKA inhibitoin increased drug sensitivity of DU145, our work demonstrated the underlying mechanism that how the acetylation enzyme regulates cancer cells survial and might provide potential therapeutic targets for prostate cancer patients in future epigenetic drug development.

Choi M, Lee S, Choi T, Lee C
Roles of the PDZ domain-binding motif of the human papillomavirus type 16 E6 on the immortalization and differentiation of primary human foreskin keratinocytes.
Virus Genes. 2014; 48(2):224-32 [PubMed] Related Publications
A number of PDZ domain-containing proteins have been identified as binding partners for the oncoprotein E6 of the high-risk type human papillomaviruses (HPVs). These include hDlg, hScrib, MAGI1, MAGI2, and MAGI3, MUPP1, 14-3-3zeta, Na/H exchange regulatory factor 1, PTPN13, TIP-2/GIPC, Tip-1, and PATJ. The PDZ domain-binding motif (-X-T-X-V) at the carboxy terminus of E6 is essential for targeting PDZ proteins for proteasomal degradation. However, contribution of degradation of PDZ proteins by E6 to HPV-induced oncogenesis is still controversial. In order to clarify potential roles of molecular interactions between high-risk HPV E6 and one of best characterized PDZ proteins, hDlg in HPV-induced transformation, we used a retroviral infection system to overexpress HPV16 E7 gene alone or together with either HPV16 E6 wild type or E6 mutant gene lacking the PDZ domain-binding motif and investigated the effect of mutating the PDZ domain-binding motif of E6 on the immortalization and differentiation of human foreskin keratinocytes (HFKs) by the high-risk type HPV E6 and E7. Although the PDZ domain-binding motif of E6 was found to be required for the efficient growth of HFKs, it was not necessary for the E6 and E7-induced immortalization of HFKs. Furthermore, the overexpression of E6 and E7 neither induced degradation nor altered cellular localization of hDlg in undifferentiated or differentiated HFKs. These data indicate that the PDZ domain-binding motif of E6 contributes to the efficient cellular growth through mechanisms other than degradation and changes in the subcellular localizations of hDlg.

Poczobutt JM, Gijon M, Amin J, et al.
Eicosanoid profiling in an orthotopic model of lung cancer progression by mass spectrometry demonstrates selective production of leukotrienes by inflammatory cells of the microenvironment.
PLoS One. 2013; 8(11):e79633 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Eicosanoids are bioactive lipid mediators derived from arachidonic acid(1) (AA), which is released by cytosolic phospholipase A2 (cPLA2). AA is metabolized through three major pathways, cyclooxygenase (COX), lipoxygenase (LO) and cytochrome P450, to produce a family of eicosanoids, which individually have been shown to have pro- or anti-tumorigenic activities in cancer. However, cancer progression likely depends on complex changes in multiple eicosanoids produced by cancer cells and by tumor microenvironment and a systematic examination of the spectrum of eicosanoids in cancer has not been performed. We used liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) to quantitate eicosanoids produced during lung tumor progression in an orthotopic immunocompetent mouse model of lung cancer, in which Lewis lung carcinoma (LLC) cells are injected into lungs of syngeneic mice. The presence of tumor increased products of both the cyclooxygenase and the lipoxygenase pathways in a time-dependent fashion. Comparing tumors grown in cPLA2 knockout vs wild-type mice, we demonstrated that prostaglandins (PGE2, PGD2 and PGF2a) were produced by both cancer cells and the tumor microenvironment (TME), but leukotriene (LTB4, LTC4, LTD4, LTE4) production required cPLA2 expression in the TME. Using flow cytometry, we recovered tumor-associated neutrophils and 2 types of tumor-associated macrophages from tumor-bearing lungs and we defined their distinct eicosanoid profiles by LC/MS/MS. The combination of flow cytometry and LC/MS/MS unravels the complexity of eicosanoid production in lung cancer and provides a rationale to develop therapeutic strategies that target select cell populations to inhibit specific classes of eicosanoids.

Wang W, Zhang M, Sun W, et al.
Reduction of decoy receptor 3 enhances TRAIL-mediated apoptosis in pancreatic cancer.
PLoS One. 2013; 8(10):e74272 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Most human pancreatic cancer cells are resistant to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. However, the mechanisms by which pancreatic cancer cells utilize their extracellular molecules to counteract the proapoptotic signaling mediated by the TNF family are largely unknown. In this study, we demonstrate for the first time that DcR3, a secreted decoy receptor that malignant pancreatic cancer cells express at a high level, acts as an extracellular antiapoptotic molecule by binding to TRAIL and counteracting its death-promoting function. The reduction of DcR3 with siRNA unmasked TRAIL and greatly enhanced TRAIL-induced apoptosis. Gemcitabine, a first-line drug for pancreatic cancer, also reduced the level of DcR3. The addition of DcR3 siRNA further enhanced gemcitabine-induced apoptosis. Notably, our in vivo study demonstrated that the therapeutic effect of gemcitabine could be enhanced via further reduction of DcR3, suggesting that downregulation of DcR3 in tumor cells could tip the balance of pancreatic cells towards apoptosis and potentially serve as a new strategy for pancreatic cancer therapy.

Quagliata L, Matter MS, Piscuoglio S, et al.
Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients.
Hepatology. 2014; 59(3):911-23 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n=52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13.
CONCLUSION: Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC.

Chanthammachat P, Promwikorn W, Pruegsanusak K, et al.
Comparative proteomic analysis of oral squamous cell carcinoma and adjacent non-tumour tissue from Thailand.
Arch Oral Biol. 2013; 58(11):1677-85 [PubMed] Related Publications
OBJECTIVE: The study was aimed at analysing and identifying the proteins that are differentially expressed in oral squamous cell carcinoma (OSCC) compared to adjacent non-tumour tissue.
MATERIALS AND METHODS: Two-dimensional (2D) sodium dodecyl sulphate-polyacrylamide gel electrophoresis accompanied by mass spectrometry (matrix-assisted laser desorption/ionisation-time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry) was used to analyse and identify the differentially expressed proteins in 10 pairs of tumours and adjacent non-tumour tissues from five cases of early-stage and five cases of late-stage OSCC. The statistical differences of the protein spots were analysed by the Wilcoxon signed-rank test. A validation study using immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was performed.
RESULTS: A total of 68 proteins (63 up-regulated, five down-regulated) were differentially expressed in early-stage disease, and 39 proteins (37 up-regulated, two down-regulated) were significantly altered in late-stage disease. Among these, 14 proteins were altered in both groups. A total of 44 proteins were identified, including heat shock proteins (HSPs: Hsp90, HSPA5 and HSPA8), keratins (K1, K6A and K17), tubulin, cofilin 1, 14-3-3σ and metabolic enzymes. These proteins are involved in various cellular processes essential for cell growth, survival and cell migration. The validation study on α-tubulin and 14-3-3σ using immunohistochemistry and KIAA1199 expression using real-time RT-PCR confirmed the results in proteomics analysis.
CONCLUSIONS: The study identified many proteins, both known and unknown, for cancer cell processes. At least two proteins, KIAA1199 and Horf6, are novel for oral cancer.

Wilkinson SE, Furic L, Buchanan G, et al.
Hedgehog signaling is active in human prostate cancer stroma and regulates proliferation and differentiation of adjacent epithelium.
Prostate. 2013; 73(16):1810-23 [PubMed] Related Publications
BACKGROUND: Contribution of stromal Hedgehog (Hh) signaling is evident in the prostate gland in mice, but needs translation to human tissues if Hh therapeutics are to be used effectively. Our goal was to determine if primary human prostate fibroblasts contain cilia, and respond to prostate Hh signaling.
METHODS: Primary human prostate cancer-associated (CAFs), and adjacent non-malignant (NPFs) fibroblasts isolated from human tissue specimens were analyzed using immunofluorescence, real-time PCR, and available array data. Cell culture and tissue recombination were used to determine responsiveness of human fibroblasts to Hh pathway manipulation and the paracrine effects of stromal Hh signaling, respectively.
RESULTS: Prostatic fibroblasts were capable of forming primary cilia, with the capacity for active Hh signaling as seen by Smo co-localization to the tip of the primary cilium. Expression of genes known to represent a signature of active Hh signaling in the prostate (especially Fgf5 and Igfbp6) were increased in CAFs compared to NPFs. The level of canonical Hh genes and prostate Hh signature genes were rarely synchronous; with lower doses of Purmorphamine/BMS-833923 regulating canonical transcription factors, and higher doses effecting prostate Hh signature genes. Grafts consisting of NPFs with constitutively active Hh signaling induced increased proliferation and dedifferentiation of adjacent non-malignant BPH-1 epithelial cells.
CONCLUSIONS: These data show that human prostatic fibroblasts have the capacity for Hh signaling and manipulation. Increased expression of a signature of prostatic Hh genes in the prostate tumor microenvironment suggests a role in the epithelial transformations driving prostate cancer (PCa).

Huang J, Stewart A, Maity B, et al.
RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis.
Oncogene. 2014; 33(27):3604-11 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.

Lee S, Qiao J, Paul P, Chung DH
Integrin β1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion.
Surgery. 2013; 154(2):369-75 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Gastrin-releasing peptide (GRP) and its receptor, GRP-R, are critically involved in neuroblastoma tumorigenesis; however, the molecular mechanisms and signaling pathways that are responsible for GRP/GRP-R-induced cell migration and invasion remain unclear. In this study, we sought to determine the cell signals involved in GRP/GRP-R-mediated neuroblastoma cell migration and invasion.
METHODS: Human neuroblastoma cell lines SK-N-SH, LAN-1, and IMR-32 were used for our study. Transwell migration and invasion assays were performed after GRP (10(-7) M) stimulation. The cDNA GEArray Microarray kit was used to determine GRP-R-induced gene expression changes. Protein and membrane expression of integrin subunits were confirmed by Western blotting and flow cytometry analysis. siRNA transfection was performed using Lipofectamine 2000. For scratch assay, a confluent monolayer of cells in 6-well plates were wounded with micropipette tip and observed microscopically at 24 to 72 h.
RESULTS: GRP increased neuroblastoma cell migration and expressions of MMP-2 whereas the TIMP-1 level decreased. GRP-R overexpression stimulated SK-N-SH cell migration and upregulated integrin α2, α3, and β1 protein as well as mRNA expression. Targeted silencing of integrin β1 inhibited cell migration.
CONCLUSION: GRP/GRP-R signaling contributes to neuroblastoma cell migration and invasion. Moreover, the integrin ß1 subunit critically regulates GRP-R-mediated neuroblastoma cell migration and invasion.

Yoon JH, Choi YJ, Choi WS, et al.
GKN1-miR-185-DNMT1 axis suppresses gastric carcinogenesis through regulation of epigenetic alteration and cell cycle.
Clin Cancer Res. 2013; 19(17):4599-610 [PubMed] Related Publications
PURPOSE: Gastrokine 1 (GKN1) functions to protect the gastric antral mucosa and promotes healing by facilitating restoration and proliferation after injury. GKN1 is downregulated in Helicobacter pylori-infected gastric epithelial cells and loss of GKN1 expression is closely associated with gastric carcinogenesis, but underlying mechanisms of the tumor-suppressing effects of GKN1 remain largely unknown.
EXPERIMENTAL DESIGN: AGS, MKN1, MKN28 gastric cancer cells and HFE-145 immortalized non-neoplastic gastric mucosal cells were transfected with GKN1 or shGKN1. We conducted molecular and functional studies of GKN1 and miR-185 and investigated the mechanisms of alteration. We also analyzed epigenetic alterations in 80 gastric cancer tissues.
RESULTS: Restoration of GKN1 protein suppressed gastric cancer cell growth by inducing endogenous miR-185 that directly targets epigenetic effectors DNMT1 and EZH2 in gastric cancer cells. In addition, ectopic expression of GKN1 upregulated Tip60 and downregulated HDAC1 in an miR-185-independent manner, thereby inducing cell-cycle arrest by regulating cell-cycle proteins in gastric cancer cells. Notably, GKN1 expression was inversely correlated with DNMT1 and EZH2 expression in a subset of 80 gastric cancer tissues and various gastric cancer cell lines. Interestingly, it was found that GKN1 exerted a synergistic anti-cancerous effect with 5-fluorouracil on tumor cell growth, which suggests a possible therapeutic intervention method for gastric cancer.
CONCLUSION: Our results show that GKN1 has an miR-185-dependent and -independent mechanism for chromatic and DNA epigenetic modification, thereby regulating the cell cycle. Thus, the loss of GKN1 function contributes to malignant transformation and proliferation of gastric epithelial cells in gastric carcinogenesis.

Shamma A, Suzuki M, Hayashi N, et al.
ATM mediates pRB function to control DNMT1 protein stability and DNA methylation.
Mol Cell Biol. 2013; 33(16):3113-24 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.

Dai C, Shi D, Gu W
Negative regulation of the acetyltransferase TIP60-p53 interplay by UHRF1 (ubiquitin-like with PHD and RING finger domains 1).
J Biol Chem. 2013; 288(27):19581-92 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Numerous studies indicate the importance of acetylation in p53-mediated stress responses upon DNA damage. We and others previously showed that TIP60 (Tat-interacting protein of 60 kDa)-mediated acetylation of p53 at K120 is crucial for p53-dependent apoptotic responses. Nevertheless, it remains unclear how TIP60-mediated effects on p53 are dynamically regulated in vivo. Here, we report that UHRF1 (ubiquitin-like with PHD and RING finger domains 1) interacts with TIP60 both in vitro and in vivo and induces degradation-independent ubiquitination of TIP60. Moreover, UHRF1 expression markedly suppresses the ability of TIP60 to acetylate p53. In contrast, RNAi-mediated knockdown of UHRF1 increases the endogenous levels of p53 acetylation at K120 and p53-mediated apoptosis is significantly enhanced in UHRF1-depleted cells. To elucidate the mechanisms of this regulation, we found that the interaction between TIP60 and p53 is severely inhibited in the presence of UHRF1, suggesting that UHRF1 modulates TIP60-mediated functions in both K120 acetylation-dependent and -independent manners. Consistent with this notion, UHRF1 knockdown promotes activation of p21 and PUMA but not MDM2. These findings demonstrate that UHRF1 is a critical negative regulator of TIP60 and suggest that UHRF1-mediated effects on p53 may contribute, at least in part, to its role in tumorigenesis.

Pirman DA, Efuet E, Ding XP, et al.
Changes in cancer cell metabolism revealed by direct sample analysis with MALDI mass spectrometry.
PLoS One. 2013; 8(4):e61379 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Biomarker discovery using mass spectrometry (MS) has recently seen a significant increase in applications, mainly driven by the rapidly advancing field of metabolomics. Instrumental and data handling advancements have allowed for untargeted metabolite analyses which simultaneously interrogate multiple biochemical pathways to elucidate disease phenotypes and therapeutic mechanisms. Although most MS-based metabolomic approaches are coupled with liquid chromatography, a few recently published studies used matrix-assisted laser desorption (MALDI), allowing for rapid and direct sample analysis with minimal sample preparation. We and others have reported that prostaglandin E3 (PGE3), derived from COX-2 metabolism of the omega-3 fatty acid eicosapentaenoic acid (EPA), inhibited the proliferation of human lung, colon and pancreatic cancer cells. However, how PGE3 metabolism is regulated in cancer cells, particularly human non-small cell lung cancer (NSCLC) cells, is not fully understood. Here, we successfully used MALDI to identify differences in lipid metabolism between two human non-small-cell lung cancer (NSCLC) cell lines, A549 and H596, which could contribute to their differential response to EPA treatment. Analysis by MALDI-MS showed that the level of EPA incorporated into phospholipids in H596 cells was 4-fold higher than A549 cells. Intriguingly, H596 cells produced much less PGE3 than A549 cells even though the expression of COX-2 was similar in these two cell lines. This appears to be due to the relatively lower expression of cytosolic phospholipase A2 (cPLA2) in H596 cells than that of A549 cells. Additionally, the MALDI-MS approach was successfully used on tumor tissue extracts from a K-ras transgenic mouse model of lung cancer to enhance our understanding of the mechanism of action of EPA in the in vivo model. These results highlight the utility of combining a metabolomics workflow with MALDI-MS to identify the biomarkers that may regulate the metabolism of omega-3 fatty acids and ultimately affect their therapeutic potentials.

Misra UK, Pizzo SV
Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.
PLoS One. 2013; 8(4):e63150 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
OBJECTIVE: In human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me-cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE2 in prostate cancer cells treated with 8-CPT-2Me-cAMP.
METHODS: We employed inhibitors of COX-2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies.
RESULTS: 8-CPT-2Me-cAMP treatment caused a 2-2.5-fold increase of p-cPLA2(S505), COX-2, and PGE2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH-23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinase(T389), and p-AKT(S473). In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2.
CONCLUSION: We show that Epac1, a downstream effector of cAMP, functions as a pro-inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling.

Lakhter AJ, Kanginakudru S, Warren S, et al.
Impaired PIASy-Tip60 signaling weakens activation of p53 in melanoma.
Melanoma Res. 2013; 23(3):213-7 [PubMed] Related Publications
The tumor suppressor p53 plays a central role in preventing tumor development by promoting transcription of genes that stall cell cycle and induce cell death. Although the majority of melanomas express wild-type p53, the molecular mechanisms that impede its activation remain unclear. We previously reported that the SUMO E3 ligase PIASy and the histone acetyltransferase Tip60 signaling cascade promote p53-dependent autophagy and apoptosis. We hypothesized that impairment in this signaling attenuates p53, thus disabling its apoptotic function in melanoma. Here, we show that human melanoma patient samples and cell lines maintain p53 expression but PIASy and/or Tip60 are frequently lost. We observed dysregulation of Tip60-mediated p53 transcription program in melanoma cell lines. Reconstitution of PIASy and Tip60 in melanoma cells increased genotoxic stress-induced apoptosis. Our study provides a clinical link of how sumoylation signaling may activate p53-mediated cell death in melanoma.

Rolfs F, Huber M, Gruber F, et al.
Dual role of the antioxidant enzyme peroxiredoxin 6 in skin carcinogenesis.
Cancer Res. 2013; 73(11):3460-9 [PubMed] Related Publications
The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8-induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis.

Wang H, Han M, Whetsell W, et al.
Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma.
Oncogene. 2014; 33(12):1558-69 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
PDZ domains represent one group of the major structural units that mediate protein interactions in intercellular contact, signal transduction and assembly of biological machineries. Tax-interacting protein (TIP)-1 protein is composed of a single PDZ domain that distinguishes TIP-1 from other PDZ domain proteins that more often contain multiple protein domains and function as scaffolds for protein complex assembly. However, the biological functions of TIP-1, especially in cell transformation and tumor progression, are still controversial as observed in a variety of cell types. In this study, we have identified ARHGEF7, a guanine nucleotide exchange factor for Rho GTPases, as one novel TIP-1-interacting protein in human glioblastoma cells. We found that the presence of TIP-1 protein is essential to the intracellular redistribution of ARHGEF7 and rhotekin, one Rho effector and the spatiotemporally coordinated activation of Rho GTPases (RhoA, Cdc42 and Rac1) in migrating glioblastoma cells. TIP-1 knockdown resulted in both aberrant localization of ARHGEF7 and rhotekin, as well as abnormal activation of Rho GTPases that was accompanied with impaired motility of glioblastoma cells. Furthermore, TIP-1 knockdown suppressed tumor cell dispersal in orthotopic glioblastoma murine models. We also observed high levels of TIP-1 expression in human glioblastoma specimens, and the elevated TIP-1 levels are associated with advanced staging and poor prognosis in glioma patients. Although more studies are needed to further dissect the mechanism(s) by which TIP-1 modulates the intracellular redistribution and activation of Rho GTPases, this study suggests that TIP-1 holds potential as both a prognostic biomarker and a therapeutic target of malignant gliomas.

Sijmons RH, Greenblatt MS, Genuardi M
Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians.
Fam Cancer. 2013; 12(2):181-7 [PubMed] Related Publications
Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance (VUS). In contrast to clearly pathogenic mutations, VUS do not firmly diagnose Lynch syndrome at the molecular level and cannot be used to identify with certainty any of the patients' asymptomatic relatives as Lynch syndrome mutation carriers. The International database that collects MMR gene variants ( www.insight-group.org/mutations ) already lists more than 1,000 different VUSs and these variants are likely the tip of the iceberg. This paper aims at introducing non-geneticist clinicians to the topic of clinical MMR gene variant interpretation. Many lines of evidence are being used to classify VUS. Some are already familiar to clinicians and others may be less familiar but are expected to become important in clinical genetics in the coming years. Clinicians can play an important role in collecting the data needed to interpret the MMR variants detected in their patients.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. KAT5, Cancer Genetics Web: http://www.cancer-genetics.org/KAT5.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 27 February, 2015     Cancer Genetics Web, Established 1999