HDAC6

Gene Summary

Gene:HDAC6; histone deacetylase 6
Aliases: HD6, JM21, CPBHM, PPP1R90
Location:Xp11.23
Summary:Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:histone deacetylase 6
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 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.

  • RNA Interference
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Apoptosis
  • Tubulin
  • Histone Deacetylase Inhibitors
  • Down-Regulation
  • Bladder Cancer
  • Immunohistochemistry
  • Drug Synergism
  • bcl-2-Associated X Protein
  • Vesicular Transport Proteins
  • Up-Regulation
  • Valproic Acid
  • Gene Knockdown Techniques
  • Cell Movement
  • HDAC6
  • Young Adult
  • Acetylation
  • Stomach Cancer
  • Gene Expression
  • Epigenetics
  • siRNA
  • RHOA
  • Thyroid Cancer
  • Estrogen Receptors
  • Cancer Gene Expression Regulation
  • Gene Expression Profiling
  • Tumor Markers
  • Two-Hybrid System Techniques
  • Tumor Microenvironment
  • Messenger RNA
  • Nuclear Proteins
  • Hydroxamic Acids
  • Breast Cancer
  • rho-Associated Kinases
  • Cell Proliferation
  • X Chromosome
  • Antineoplastic Agents
  • Histone Deacetylases
Tag cloud generated 21 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: HDAC6 (cancer-related)

Sen A, Nelson TJ, Alkon DL
ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.
J Neurosci. 2015; 35(19):7538-51 [PubMed] Related Publications
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.

Shagisultanova E, Gaponova AV, Gabbasov R, et al.
Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases.
Gene. 2015; 567(1):1-11 [PubMed] Article available free on PMC after 01/08/2016 Related Publications
Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

Zhang L, Liu N, Xie S, et al.
HDAC6 regulates neuroblastoma cell migration and may play a role in the invasion process.
Cancer Biol Ther. 2014; 15(11):1561-70 [PubMed] Related Publications
Neuroblastoma is one of the most prevalent pediatric extracranial solid tumors and is often diagnosed after dissemination has occurred. Despite recent advances in multimodal therapies of this malignancy, its therapeutic efficacy remains poor. Novel treatment strategies are thus in great need. Herein, we demonstrate that histone deacetylase 6 (HDAC6), a member of the deacetylase family that is localized predominantly in the cytoplasm, is involved in neuroblastoma dissemination. HDAC6 expression in neuroblastoma tissue samples varied with the site of the tumor. HDAC6 showed little impact on the proliferation of neuroblastoma cells. Instead, downregulation of HDAC6 expression by RNA interference or inhibition of its catalytic activity by the pharmacological inhibitor tubacin significantly decreased the migration of 3 human malignant neuroblastoma cell lines and reduced the invasion ability of one of the 3 cell lines, but only slightly affected the migration and invasion of human normal brain glial cells. Our data further revealed that the regulation of neuroblastoma cell migration by HDAC6 was mediated by its effects on cell polarization and adhesion. These findings suggest a role for HDAC6 in neuroblastoma dissemination and a potential of using HDAC6 inhibitors for the treatment of this malignancy.

Mithraprabhu S, Kalff A, Chow A, et al.
Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma.
Epigenetics. 2014; 9(11):1511-20 [PubMed] Related Publications
Histone deacetylases (HDAC) control gene expression through their ability to acetylate proteins, thereby influencing a diverse range of cellular functions. Class I HDAC (HDAC1-3 and 8) and HDAC6 are predominantly upregulated in malignancies and their altered expression in some cancers has a significant prognostic implication. The expression and prognostic consequence of dysregulated Class I HDAC and HDAC6, key players in multiple myeloma (MM), are unknown. This study hypothesized that HDAC are dysregulated in MM and patients with high expression have significantly poorer prognostic outcomes. Quantitative PCR for 11 HDAC (Class I, II, and IV) was performed in genetically heterogeneous human myeloma cell lines (HMCL) and primary MM and compared to normal plasma cells (PC). In HMCL, HDAC1-3 and 8 (Class I), and HDAC5 and HDAC10 (Class II) were significantly upregulated compared to normal PC. In primary MM, the median expression level of all of the HDAC, except HDAC1 and HDAC11, were elevated when compared to normal PC. Patients with higher levels of HDAC1-3, HDAC4, HDAC6, and HDAC11 transcripts demonstrated a significantly shorter progression-free survival (PFS). Immunohistochemical staining for HDAC1 and HDAC6 on bone marrow trephines from a uniformly treated cohort of transplant eligible MM patients revealed that HDAC1 protein was detectable in most patients and that higher levels of MM cell HDAC1 protein expression (≥90 % versus ≤20 % MM cell positivity) correlated with both shorter PFS (P = 0 .07) and shorter overall survival (P = 0 .003). Conversely, while the majority of patients expressed HDAC6, there was no correlation between HDAC6 levels and patient outcome. Together, these results indicate that overexpression of Class I HDAC, particularly HDAC1, is associated with poor prognosis in MM.

Lakshmaiah KC, Jacob LA, Aparna S, et al.
Epigenetic therapy of cancer with histone deacetylase inhibitors.
J Cancer Res Ther. 2014 Jul-Sep; 10(3):469-78 [PubMed] Related Publications
Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III HDAC and Class IV (HDAC11). Histone Deacetylase Inhibitors (HDACI) exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates. The effects of HDACI on gene transcription are complex. They cause cell cycle arrest, inhibit DNA repair, induce apoptosis and acetylate non histone proteins causing downstream alterations in gene expression. HDACI are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two. They are classified into four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides. This review describes the clinical utility of HDACI as monotherapy as well as combination therapy with other treatment modalities such as chemotherapy and radiotherapy. Adverse effects and shortcomings of treatment with HDACI are also discussed in detail.

Dere R, Perkins AL, Bawa-Khalfe T, et al.
β-catenin links von Hippel-Lindau to aurora kinase A and loss of primary cilia in renal cell carcinoma.
J Am Soc Nephrol. 2015; 26(3):553-64 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
von Hippel-Lindau (VHL) gene mutations are associated with clear cell renal cell carcinoma (ccRCC). A hallmark of ccRCC is loss of the primary cilium. Loss of this key organelle in ccRCC is caused by loss of VHL and associated with increased Aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) activities, which drive disassembly of the primary cilium. However, the underlying mechanism by which VHL loss increases AURKA levels has not been clearly elucidated, although it has been suggested that hypoxia-inducible factor-1α (HIF-1α) mediates increased AURKA expression in VHL-null cells. By contrast, we found that elevated AURKA expression is not increased by HIF-1α, suggesting an alternate mechanism for AURKA dysregulation in VHL-null cells. We report here that AURKA expression is driven by β-catenin transcription in VHL-null cells. In a panel of RCC cell lines, we observed nuclear accumulation of β-catenin and increased AURKA signaling to HDAC6. Moreover, HIF-1α inhibited AURKA expression by inhibiting β-catenin transcription. VHL knockdown activated β-catenin and elevated AURKA expression, decreased primary cilia formation, and caused significant shortening of cilia length in cells that did form cilia. The β-catenin responsive transcription inhibitor iCRT14 reduced AURKA levels and rescued ciliary defects, inducing a significant increase in primary cilia formation in VHL-deficient cells. These data define a role for β-catenin in regulating AURKA and formation of primary cilia in the setting of VHL deficiency, opening new avenues for treatment with β-catenin inhibitors to rescue ciliogenesis in ccRCC.

Dasmahapatra G, Patel H, Friedberg J, et al.
In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells.
Mol Cancer Ther. 2014; 13(12):2886-97 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib were examined in non-Hodgkin lymphoma (NHL) models, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2-M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with carfilzomib and ricolinostat increased reactive oxygen species (ROS), whereas the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34(+) cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by carfilzomib. shRNA knockdown of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced carfilzomib-ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to carfilzomib and ricolinostat also markedly downregulated the cargo-loading protein HR23B. Moreover, HR23B knockdown significantly increased carfilzomib- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with carfilzomib and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that carfilzomib and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL.

Steg AD, Burke MR, Amm HM, et al.
Proteasome inhibition reverses hedgehog inhibitor and taxane resistance in ovarian cancer.
Oncotarget. 2014; 5(16):7065-80 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The goal of this study was to determine whether combined targeted therapies, specifically those against the Notch, hedgehog and ubiquitin-proteasome pathways, could overcome ovarian cancer chemoresistance. Chemoresistant ovarian cancer cells were exposed to gamma-secretase inhibitors (GSI-I, Compound E) or the proteasome inhibitor bortezomib, alone and in combination with the hedgehog antagonist, LDE225. Bortezomib, alone and in combination with LDE225, was evaluated for effects on paclitaxel efficacy. Cell viability and cell cycle analysis were assessed by MTT assay and propidium iodide staining, respectively. Proteasome activity and gene expression were determined by luminescence assay and qPCR, respectively. Studies demonstrated that GSI-I, but not Compound E, inhibited proteasome activity, similar to bortezomib. Proteasome inhibition decreased hedgehog target genes (PTCH1, GLI1 and GLI2) and increased LDE225 sensitivity in vitro. Bortezomib, alone and in combination with LDE225, increased paclitaxel sensitivity through apoptosis and G2/M arrest. Expression of the multi-drug resistance gene ABCB1/MDR1 was decreased and acetylation of α-tubulin, a marker of microtubule stabilization, was increased following bortezomib treatment. HDAC6 inhibitor tubastatin-a demonstrated that microtubule effects are associated with hedgehog inhibition and sensitization to paclitaxel and LDE225. These results suggest that proteasome inhibition, through alteration of microtubule dynamics and hedgehog signaling, can reverse taxane-mediated chemoresistance.

Park SJ, Kim JK, Bae HJ, et al.
HDAC6 sustains growth stimulation by prolonging the activation of EGF receptor through the inhibition of rabaptin-5-mediated early endosome fusion in gastric cancer.
Cancer Lett. 2014; 354(1):97-106 [PubMed] Related Publications
The aberrant regulation of histone deacetylase 6 (HDAC6) contributes to malignant progression in various types of cancer, but the mechanism underlying gastric carcinogenesis remains unknown. Aberrant HDAC6 overexpression was observed in a subset of human gastric cancer cells. HDAC6 knockdown caused the significant inhibition of gastric cancer cell growth without affecting the transition of cell cycles or the processing of cell death. We demonstrate that an increase in epidermal growth factor receptor (EGFR) signaling through decreased EGFR degradation was mediated by HDAC6 in gastric carcinogenesis. These results establish a molecular mechanism responsible for oncogenic HDAC6, explaining how EGFR signaling induced by the growth factor is sustained during the malignant progression of gastric cancer.

Götze S, Coersmeyer M, Müller O, Sievers S
Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells.
Int J Oncol. 2014; 45(4):1715-23 [PubMed] Related Publications
Histone deacetylase inhibitors (HDIs) specifically affect cancer cells by inducing cell cycle arrest, activate apoptotic pathways and re-activate epigenetically silenced tumor suppressor genes, but their pleiotropic mode of action is not fully understood. Despite the clinical effects of HDIs in the treatment of hematological malignancies, their potency against solid tumors is still unclear. We investigated the effects and mechanisms of HDI action in colorectal carcinoma cell lines with an activated Wnt signaling pathway, which is implicated in different aspects of tumorigenesis, including cell proliferation, apoptosis, angiogenesis and metastasis. We assessed the effects of HDI treatment in colorectal carcinoma cell lines by measuring histone hyperacetylation, cell viability and expression of Wnt target genes. Upon treatment with HDIs of the hydroxamate class, we found attenuation of Wnt signaling with concomitant induction of apoptosis and colorectal cancer cell death. Strikingly, the effects of HDIs on Wnt signaling were independent of histone hyperacetylation, thus we investigated the role of non-histone target proteins of histone deacetylases (HDACs). The compounds TSA and SAHA induced a rapid proteasome-dependent depletion of the Wnt transcription factor TCF7L2, which may be mediated by inhibition of HDAC 6 and 10. Our findings provide a molecular rationale for the use of HDIs against colorectal carcinomas with activated Wnt signaling.

Wilson-Edell KA, Kehasse A, Scott GK, et al.
RPL24: a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cancer cell growth.
Oncotarget. 2014; 5(13):5165-76 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Partial loss of large ribosomal subunit protein 24 (RPL24) function is known to protect mice against Akt or Myc-driven cancers, in part via translational inhibition of a subset of cap(eIF4E)-dependently translated mRNAs. The role of RPL24 in human malignancies is unknown. By analyzing a public dataset of matched human breast cancers and normal mammary tissue, we found that breast cancers express significantly more RPL24 than matched normal breast samples. Depletion of RPL24 in breast cancer cells by >70% reduced cell viability by 80% and decreased protein expression of the eIF4E-dependently translated proteins cyclin D1 (75%), survivin (46%) and NBS1 (30%) without altering GAPDH or beta-tubulin levels. RPL24 knockdown also reduced 80S subunit levels relative to 40S and 60S levels. These effects on expression of eIF4E-dependent proteins and ribosome assembly were mimicked by 2-24 h treatment with the pan-HDACi, trichostatin A (TSA), which induced acetylation of 15 different polysome-associated proteins including RPL24. Furthermore, HDAC6-selective inhibition or HDAC6 knockdown induced ribosomal protein acetylation. Via mass spectrometry, we found that 60S-associated, but not, polysome-associated, RPL24 undergoes HDACi-induced acetylation on K27. Thus, RPL24 K27 acetylation may play a role in ribosome assembly. These findings point toward a novel acetylation-dependent polysome assembly mechanism regulating tumorigenesis.

Tu Y, Hershman DL, Bhalla K, et al.
A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.
Breast Cancer Res Treat. 2014; 146(1):145-52 [PubMed] Related Publications
Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Hussong M, Börno ST, Kerick M, et al.
The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.
Cell Death Dis. 2014; 5:e1195 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti-cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress.

Rosik L, Niegisch G, Fischer U, et al.
Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells.
Cancer Biol Ther. 2014; 15(6):742-57 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Epigenetic modifiers such as histone deacetylases (HDACs) have come into focus as novel drug targets for cancer therapy due to their functional role in tumor progression. Since common pan-HDAC inhibitors have adverse side effects and minor anti-cancer activity against solid tumors, enzyme-specific inhibitors were developed. HDAC6 is especially well-suited for specific inhibition due to its unique domain structure and mode of action and has been suggested to provide an exceptionally suitable target for cancer therapy. However, expression and function of HDACs have been insufficiently studied in urothelial cancers (UC), a disease urgently requiring new therapeutic approaches. The present study sought to evaluate HDAC6 as a target for treatment of urothelial cancers with enzyme-specific inhibitors. We observed moderate HDAC6 overexpression in urothelial cancer tissues and a broad range of expression in urothelial cancer cell lines. In the cell lines Tubacin was the most potent inhibitor, compared with Tubastatin and ST-80, but still active only at high micromolar concentrations. HDAC6 expression levels correlated poorly with sensitivity to enzyme inhibition. Combined treatments with heat shock, HSP90 inhibition by 17-AAG, proteasome inhibition by bortezomib, or DNA-damaging agents did not result in significant synergistic effects. Experiments with siRNA-mediated knockdown further underlined that urothelial cancer cells do not critically depend on HDAC6 expression for survival.

Ferrer I, Mohan P, Chen H, et al.
Tubers from patients with tuberous sclerosis complex are characterized by changes in microtubule biology through ROCK2 signalling.
J Pathol. 2014; 233(3):247-57 [PubMed] Related Publications
Most patients with tuberous sclerosis complex (TSC) develop cortical tubers that cause severe neurological disabilities. It has been suggested that defects in neuronal differentiation and/or migration underlie the appearance of tubers. However, the precise molecular alterations remain largely unknown. Here, by combining cytological and immunohistochemical analyses of tubers from nine TSC patients (four of them diagnosed with TSC2 germline mutations), we show that alteration of microtubule biology through ROCK2 signalling contributes to TSC neuropathology. All tubers showed a larger number of binucleated neurons than expected relative to control cortex. An excess of normal and altered cytokinetic figures was also commonly observed. Analysis of centrosomal markers suggested increased microtubule nucleation capacity, which was supported by the analysis of an expression dataset from cortical tubers and control cortex, and subsequently linked to under-expression of Rho-associated coiled-coil containing kinase 2 (ROCK2). Thus, augmented microtubule nucleation capacity was observed in mouse embryonic fibroblasts and human fibroblasts deficient in the Tsc2/TSC2 gene product, tuberin. Consistent with ROCK2 under-expression, microtubule acetylation was found to be increased with tuberin deficiency; this alteration was abrogated by rapamycin treatment and mimicked by HDAC6 inhibition. Together, the results of this study support the hypothesis that loss of TSC2 expression can alter microtubule organization and dynamics, which, in turn, deregulate cell division and potentially impair neuronal differentiation.

Li D, Sun X, Zhang L, et al.
Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells.
Protein Cell. 2014; 5(3):214-23 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.

Yang PH, Zhang L, Zhang YJ, et al.
HDAC6: physiological function and its selective inhibitors for cancer treatment.
Drug Discov Ther. 2013; 7(6):233-42 [PubMed] Related Publications
Acetylation and deacetylation of histones are important in regulating gene expression and play a key role in modification of gene transcription. Specific HDACs isoforms can be regarded as a target for cancer therapy avoiding side-effects, HDAC6 with a unique physiological function and structure has become a hot issue recently. The unique isoform HDAC6 is involved in tumorigenesis, development and metastasis through tubulin, HSP90, invasin and ubiquitin-protein. Here we review the structure elements, biological function, and recent selective inhibitors of HDAC6, and study the structure-activity and structure-selectivity relationship.

Lwin T, Zhao X, Cheng F, et al.
A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas.
J Clin Invest. 2013; 123(11):4612-26 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, clonogenicity, and induction of histone deacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma cell lines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion–mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets.

Fang LT, Lee S, Choi H, et al.
Comprehensive genomic analyses of a metastatic colon cancer to the lung by whole exome sequencing and gene expression analysis.
Int J Oncol. 2014; 44(1):211-21 [PubMed] Related Publications
We performed whole exome sequencing and gene expression analysis on a metastatic colon cancer to the lung, along with the adjacent normal tissue of the lung. Whole exome sequencing uncovered 71 high-confidence non‑synonymous mutations. We selected 16 mutation candidates, and 13 out of 16 mutations were validated by targeted deep sequencing using the Ion Torrent PGM customized AmpliSeq panel. By integrating mutation, copy number and gene expression microarray data, we identified a JAZF1 mutation with a gain-of-copy, suggesting its oncogenic potential for the lung metastasis from colon cancer. Our pathway analyses showed that the identified mutations closely reflected characteristics of the metastatic site (lung) while mRNA gene expression patterns kept genetic information of its primary tumor (colon). The most significant gene expression network was the 'Colorectal Cancer Metastasis Signaling', containing 6 (ADCY2, ADCY9, APC, GNB5, K-ras and LRP6) out of the 71 mutated genes. Some of these mutated genes (ADCY9, ADCY2, GNB5, K-ras, HDAC6 and ARHGEF17) also belong to the 'Phospholipase C Signaling' network, which suggests that this pathway and its mutated genes may contribute to a lung metastasis from colon cancer.

Pavlik CM, Wong CY, Ononye S, et al.
Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp.
J Nat Prod. 2013; 76(11):2026-33 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
A dark brown tuft-forming cyanobacterium, morphologically resembling the genus Symploca, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for Symploca and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (1), which has several structural features in common with suberoylanilide hydroxamic acid [(2), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of 1 and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (1 and 2), were achieved and evaluated for their HDAC activity and specificity.

Ajeawung NF, Faure R, Jones C, Kamnasaran D
Preclinical evaluation of dipotassium bisperoxo (picolinato) oxovanadate V for the treatment of pediatric low-grade gliomas.
Future Oncol. 2013; 9(8):1215-29 [PubMed] Related Publications
AIM: The treatment of pediatric low-grade gliomas with current treatment modalities still remains ineffective among a subset of patients; hence, justifying the need to further investigate more effective therapies. Dipotassium bisperoxo (picolinato) oxovanadate V (Bpv[pic]), is a derivative of the trace metal vanadium and a potent inhibitor of protein tyrosine phosphatases, which are important mediators of oncogenic and tumor suppressive activities in cancers. In this study, we undertook a preclinical evaluation of the antineoplastic functions of Bpv(pic) in the treatment of pediatric low-grade gliomas.
MATERIALS & METHODS: We utilized pediatric low-grade glioma cell lines (Res186, Res259 and R286) in a wide variety of cancer assays to determine whether Bpv(pic) can abrogate the neoplastic properties of these cells.
RESULTS: Our preclinical evaluation of the antineoplastic properties of Bpv(pic) in pediatric low-grade gliomas reveals a significant dose-dependent decrease in cell viability as a consequence of decreased proliferation and sustained induction of growth arrest and apoptosis. Bpv(pic) significantly decreases cell migration/invasion and anchorage-independent growth in soft agarose. Within cells, Bpv(pic) functions by attenuating CDC25A activity, and by decreasing the expression of multiple protein tyrosine phosphatases, DNA repair genes, microtubule-associated genes, such as PLK1, AURKA and HDAC6, and conversely augmenting the expression of proapoptotic mediators such as BAK, AIFM and CTSL1.
CONCLUSION: Collectively, our data strongly suggest novel evidence of Bpv(pic) being a potent antineoplastic drug and a suitable alternative for the treatment of pediatric low-grade gliomas.

Giaginis C, Alexandrou P, Delladetsima I, et al.
Clinical significance of histone deacetylase (HDAC)-1, HDAC-2, HDAC-4, and HDAC-6 expression in human malignant and benign thyroid lesions.
Tumour Biol. 2014; 35(1):61-71 [PubMed] Related Publications
Histone deacetylases (HDACs) have been associated with human malignant tumor development and progression, and HDAC inhibitors are currently being explored as anticancer agents in clinical trials. The present study aimed to evaluate the clinical significance of HDAC-1, HDAC-2, HDAC-4, and HDAC-6 proteins' expression in human malignant and benign thyroid lesions. HDAC-1, HDAC-2, HDAC-4, and HDAC-6 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 74 patients with benign and malignant thyroid lesions. Enhanced HDAC-2 and HDAC-6 expression was significantly more frequently observed in malignant, compared to benign, thyroid lesions (p = 0.0042 and p = 0.0069, respectively). Enhanced HDAC-2, HDAC-4, and HDAC-6 expression was significantly more frequently observed in cases with papillary carcinoma compared to hyperplastic nodules (p = 0.0065, p = 0.0394, and p = 0.0061, respectively). In malignant thyroid lesions, HDAC-1, HDAC-4, and HDAC-6 expression was significantly associated with tumor size (p = 0.0169, p = 0.0056, and p = 0.0234, respectively); HDAC-2 expression with lymphatic and vascular invasion (p = 0.0299 and p = 0.0391, respectively); and HDAC-4 expression with capsular invasion (p = 0.0464). The cellular pattern of HDAC-1 and HDAC-2 distribution (nuclear vs. nuclear and cytoplasmic) presented a distinct discrimination between malignant and benign thyroid lesions (p = 0.0030 and p = 0.0028, respectively) as well as between papillary carcinoma and hyperplastic nodules (p = 0.0036 and p = 0.0028, respectively). HDAC-1, HDAC-2, HDAC-4, and HDAC-6 may be associated with the malignant thyroid transformation and could be considered as useful biomarkers and possible therapeutic targets in this neoplasia.

Komatsu S, Moriya S, Che XF, et al.
Combined treatment with SAHA, bortezomib, and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells.
Biochem Biophys Res Commun. 2013; 437(1):41-7 [PubMed] Related Publications
The ubiquitin-proteasome pathway and the autophagy-lysosome pathway are two major intracellular protein degradation systems. We previously reported that clarithromycin (CAM) blocks autophagy flux, and that combined treatment with CAM and proteasome inhibitor bortezomib (BZ) enhances ER-stress-mediated apoptosis in breast cancer cells, whereas treatment with CAM alone results in almost no cytotoxicity. Since HDAC6 is involved in aggresome formation, which is recognized as a cytoprotective response serving to sequester misfolded proteins and facilitate their clearance by autophagy, we further investigated the combined effect of vorinostat (suberoylanilide hydroxamic acid (SAHA)), which has a potent inhibitory effect for HDAC6, with CAM and BZ in breast cancer cell lines. SAHA exhibited some cytotoxicity along with an increased acetylation level of α-tubulin, a substrate of HDAC6. Combined treatment of SAHA, CAM, and BZ potently enhanced the apoptosis-inducing effect compared with treatment using each reagent alone or a combination of two of the three. Expression levels of ER-stress-related genes, including the pro-apoptotic transcription factor CHOP (GADD153), were maximally induced by the simultaneous combination of three reagents. Like breast cancer cell lines, a wild-type murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and maximally up-regulated Chop after combined treatment with SAHA, CAM, and BZ; however, a Chop knockout MEF cell line almost completely canceled this enhanced effect. The specific HDAC6 inhibitor tubacin also exhibited a pronounced cytocidal effect with a combination of CAM plus BZ. These data suggest that simultaneous targeting of intracellular proteolytic pathways and HDAC6 enhances ER-stress-mediated apoptosis in breast cancer cells.

Tien SC, Chang ZF
Oncogenic Shp2 disturbs microtubule regulation to cause HDAC6-dependent ERK hyperactivation.
Oncogene. 2014; 33(22):2938-46 [PubMed] Related Publications
Deregulation of Shp2, a non-receptor tyrosine phosphatase, causes hyperactivation of extracellular signal-regulated kinase (ERK), leading to growth abnormality. Here, we show that inhibition of RhoA-Dia is sufficient to upregulate ERK activation in epithelial cells. Oncogenic Shp2 expression attenuates RhoA-Dia signaling, by which microtubule (MT) is destabilized with reduced level of acetylation. Either MT stabilization, silencing of histone deacetylase 6 (HDAC6) or enforcing RhoA-Dia signal prevents oncogenic Shp2-induced ERK hyperactivation. We provide evidence that downregulation of RhoA-Dia-EB1 pathway by oncogenic Shp2 leads to HDAC6-mediated reduction in MT acetylation, in turn affecting ERK regulation. In response to serum stimulation, cells expressing wild-type Shp2 display transient ERK activation. In contrast, cells expressing oncogenic Shp2 have prolonged ERK activation. HDAC6 inhibition diminishes sustained activation of ERK and slows down the growth of these cells. Likewise, in human cancer cells, blocking Shp2 increases MT acetylation and decreases ERK phosphorylation, which are reversed by inhibition of Dia. As such, HDAC6 inhibition in these cells also reduces ERK activity. Our findings link MT regulation by HDAC6 to oncogenic Shp2 and ERK regulation, implicating the therapeutic potential of HDAC6 inhibitor in diseases involving Shp2 deregulation.

Rajendran P, Kidane AI, Yu TW, et al.
HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates.
Epigenetics. 2013; 8(6):612-23 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Histone deacetylases (HDACs) and acetyltransferases have important roles in the regulation of protein acetylation, chromatin dynamics and the DNA damage response. Here, we show in human colon cancer cells that dietary isothiocyanates (ITCs) inhibit HDAC activity and increase HDAC protein turnover with the potency proportional to alkyl chain length, i.e., AITC < sulforaphane (SFN) < 6-SFN < 9-SFN. Molecular docking studies provided insights into the interactions of ITC metabolites with HDAC3, implicating the allosteric site between HDAC3 and its co-repressor. ITCs induced DNA double-strand breaks and enhanced the phosphorylation of histone H2AX, ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase-2 (CHK2). Depending on the ITC and treatment conditions, phenotypic outcomes included cell growth arrest, autophagy and apoptosis. Coincident with the loss of HDAC3 and HDAC6, as well as SIRT6, ITCs enhanced the acetylation and subsequent degradation of critical repair proteins, such as CtIP, and this was recapitulated in HDAC knockdown experiments. Importantly, colon cancer cells were far more susceptible than non-cancer cells to ITC-induced DNA damage, which persisted in the former case but was scarcely detectable in non-cancer colonic epithelial cells under the same conditions. Future studies will address the mechanistic basis for dietary ITCs preferentially exploiting HDAC turnover mechanisms and faulty DNA repair pathways in colon cancer cells vs. normal cells.

Yang MH, Laurent G, Bause AS, et al.
HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS.
Mol Cancer Res. 2013; 11(9):1072-7 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
UNLABELLED: Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.
IMPLICATIONS: This study suggests that altering K-RAS acetylation is a feasible approach to limiting tumorigenic potential.

Li N, Tie XJ, Liu PJ, et al.
Effects of down-regulation of HDAC6 expression on proliferation, cell cycling and migration of esophageal squamous cell carcinoma cells and related molecular mechanisms.
Asian Pac J Cancer Prev. 2013; 14(2):685-9 [PubMed] Related Publications
OBJECTIVE: To study the effects of down-regulation of HDAC6 expression on proliferation, cell cycling and migration of esophageal squamous cell carcinoma (ESCC) cells and related molecular mechanisms.
METHODS: ESCC cell line EC9706 cells were randomly divided into untreated (with no transfection), control siRNA (transfected with control siRNA) and HDAC6 siRNA (transfected with HDAC6 small interfering RNA) groups. Effects of HDAC6 siRNA interference on expression of HDAC6 mRNA and protein in EC9706 cells were investigated by semi-quantitative RT-PCR, Western blotting and immunocytochemistry methods. Effects of down-regulation of HDAC6 expression on cell proliferation, cell cycle, and cell migration were studied using a CCK-8 kit, flow cytometry and Boyden chambers, respectively. Changes of mRNA and protein expression levels of cell cycle related factor (p21) and cell migration related factor (E-cadherin) were investigated by semi- quantitative RT-PCR and Western blotting methods.
RESULTS: After transfection of HDAC6 siRNA, the expression of HDAC6 mRNA and protein in EC9706 cells was significantly downregulated. In the HDAC6 siRNA group, cell proliferation was markedly inhibited, the percentage of cells in G0/G1 phase evidently increased and the percentage of cells in S phase decreased, and the number of migrating cells significantly and obviously decreased. The mRNA and protein expression levels of p21 and E-cadherin in the HDAC6 siRNA group were significantly higher than those in the untreated group and the control siRNA group, respectively.
CONCLUSIONS: HDAC6 siRNA can effectively downregulate the expression of HDAC6 mRNA and protein in EC9706 cells. Down-regulation of HDAC6 expression can obviously inhibit cell proliferation, arrest cell cycling in the G0/G1 phase and reduce cell migration. The latter two functions may be closely related with the elevation of mRNA and protein expression of p21 and E-cadherin.

Ding G, Liu HD, Huang Q, et al.
HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity.
FEBS Lett. 2013; 587(7):880-6 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation, cell cycle progression and developmental events. However, its biological roles in the development of HCC remain largely unexplored. In the present study, we found that mRNA and protein levels of HDAC6 were up-regulated in HCC tissues and cell lines. The proinflammatory cytokines, which were up-regulated in the human HCC microenvironment, increased HDAC6 expression through a proximal NF-kappaB binding site on the HDAC6 gene promoter. Furthermore, overexpression of HDAC6 could promote cell proliferation in HCC cell lines. In contrast, HDAC6 knockdown using small interfering RNA inhibited cell proliferation. At the molecular level, we demonstrated that HDAC6 could interact with p53 and attenuate its transcriptional activity through promotion of its degradation. Therefore, our results suggest a previously unknown HDAC6-p53 molecular network controlling HCC development.

Kaliszczak M, Trousil S, Åberg O, et al.
A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.
Br J Cancer. 2013; 108(2):342-50 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: This study investigates whether a histone deacetylase subtype 6 (HDAC6) inhibitor could be used in the treatment of solid tumours.
METHODS: We evaluated the effect of a novel inhibitor, C1A, on HDAC6 biochemical activity and cell growth. We further examined potential of early noninvasive imaging of cell proliferation by [(18)F]fluorothymidine positron emission tomography ([(18)F]FLT-PET) to detect therapy response.
RESULTS: C1A induced sustained acetylation of HDAC6 substrates, α-tubulin and HSP90, compared with current clinically approved HDAC inhibitor SAHA. C1A induced apoptosis and inhibited proliferation of a panel of human tumour cell lines from different origins in the low micromolar range. Systemic administration of the drug inhibited the growth of colon tumours in vivo by 78%. The drug showed restricted activity on gene expression with <0.065% of genes modulated during 24 h of treatment. C1A treatment reduced tumour [(18)F]FLT uptake by 1.7-fold at 48 h, suggesting that molecular imaging could provide value in future studies of this compound.
CONCLUSION: C1A preferentially inhibits HDAC6 and modulates HDAC6 downstream targets leading to growth inhibition of a diverse set of cancer cell lines. This property together with the favourable pharmacokinetics and efficacy in vivo makes it a candidate for further pre-clinical and clinical development.

McLornan D, Hay J, McLaughlin K, et al.
Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia.
Br J Haematol. 2013; 160(2):188-98 [PubMed] Related Publications
Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down-regulation of c-FLIP(L) and c-FLIP(S) proteins using siRNA induced apoptosis in U937 and NB-4 AML cells, but not K562 or OCI-AML3 cells. However, dual c-FLIP(L/S) downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor-related apoptosis-inducing ligand (rTRAIL). Moreover, specific downregulation of c-FLIP(L) was found to recapitulate the phenotypic effects of dual c-FLIP(L/S) downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down-regulate c-FLIP(L) expression by transcriptional and post-transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c-FLIP(L) down-regulation. These results suggest that c-FLIP(L) may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.

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