Gene Summary

Gene:HDAC6; histone deacetylase 6
Aliases: HD6, JM21, CPBHM, PPP1R90
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, HGNC, Ensembl, GeneCard, Gene
Protein:histone deacetylase 6
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (71)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 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.

  • Histone Deacetylase 6
  • Virus Replication
  • Zinc Finger E-box-Binding Homeobox 1
  • Stomach Cancer
  • Vegetables
  • Cancer Gene Expression Regulation
  • siRNA
  • X Chromosome
  • Histone Deacetylase Inhibitors
  • Estrogen Receptors
  • Signal Transduction
  • Antineoplastic Agents
  • Hydroxamic Acids
  • YY1 Transcription Factor
  • TOR Serine-Threonine Kinases
  • Tumor Microenvironment
  • Apoptosis
  • Bladder Cancer
  • Cell Proliferation
  • Thrombocythemia, Essential
  • Repressor Proteins
  • Vesicular Transport Proteins
  • Breast Cancer
  • Young Adult
  • Nucleosomes
  • Skin Cancer
  • RB1
  • RHOA
  • TNF-Related Apoptosis-Inducing Ligand
  • rho-Associated Kinases
  • Thyroid Cancer
  • Acetylation
  • RNA Interference
  • Two-Hybrid System Techniques
  • Up-Regulation
  • Histone Deacetylases
  • Tumor Stem Cell Assay
  • Protein Kinase Inhibitors
  • HDAC6
  • Transfection
  • Vorinostat
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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)

Zhang J, Liu M, Liu W, Wang W
Ras-ERK1/2 signalling promotes the development of osteosarcoma through regulation of H4K12ac through HAT1.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1207-1215 [PubMed] Related Publications
Histone H4 acetylation at lysine 12 (H4K12ac) has been reported to be associated with the poor prognosis of pancreatic cancer. The study intends to study whether H4K12ac participates in regulating the carcinogenic effect of Ras-ERK1/2 on osteosarcoma (OS). The plasmids of pEGFP-N1, pEGFP-Ras

Urdiciain A, Erausquin E, Meléndez B, et al.
Tubastatin A, an inhibitor of HDAC6, enhances temozolomide‑induced apoptosis and reverses the malignant phenotype of glioblastoma cells.
Int J Oncol. 2019; 54(5):1797-1808 [PubMed] Related Publications
Glioblastoma or grade IV astrocytoma is the most common and lethal form of glioma. Current glioblastoma treatment strategies use surgery followed by chemotherapy with temozolomide. Despite this, numerous glioblastoma cases develop resistance to temozolomide treatments, resulting in a poor prognosis for the patients. Novel approaches are being investigated, including the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates α‑tubulin, and whose overexpression in glioblastoma is associated with the loss of primary cilia. The aim of the present study was to treat glioblastoma cells with a selective HDAC6 inhibitor, tubastatin A, to determine if the malignant phenotype may be reverted. The results demonstrated a notable increase in acetylated α‑tubulin levels in treated cells, which associated with downregulation of the sonic hedgehog pathway, and may hypothetically promote ciliogenesis in those cells. Treatment with tubastatin A also reduced glioblastoma clonogenicity and migration capacities, and accelerated temozolomide‑induced apoptosis. Finally, HDAC6 inhibition decreased the expression of mesenchymal markers, contributing to reverse epithelial‑mesenchymal transition in glioblastoma cells.

Ishigami-Yuasa M, Ekimoto H, Kagechika H
Class IIb HDAC Inhibition Enhances the Inhibitory Effect of Am80, a Synthetic Retinoid, in Prostate Cancer.
Biol Pharm Bull. 2019; 42(3):448-452 [PubMed] Related Publications
Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/β agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.

Hu Y, Dai M, Zheng Y, et al.
Epigenetic suppression of E-cadherin expression by Snail2 during the metastasis of colorectal cancer.
Clin Epigenetics. 2018; 10(1):154 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transcription factor Snail2 is a repressor of E-cadherin expression during carcinogenesis; however, the specific mechanisms involved in this process in human colorectal cancer (CRC) remain largely unknown.
METHOD: We checked the expression of Snail2 in several clinical CRC specimens. Then, we established Snail2-overexpressing and knockdown cell lines to determine the function of Snail2 during EMT and metastasis processes in CRC. In addition, we used luciferase reporter assay to explore how Snail2 inhibits the expression of E-cadherin and induces EMT.
RESULTS: We found that the expression of Snail2 was higher in clinical specimens of colorectal cancer (CRC) compared to non-cancerous tissues. Overexpression of Snail2 induced migration and metastatic properties in CRC cells in vitro and in vivo. Furthermore, overexpression of Snail2 promoted the occurrence of the epithelial-mesenchymal transition (EMT), downregulating the expression of E-cadherin and upregulating that of vimentin. Specifically, Snail2 could interact with HDAC6 and then recruited HDAC6 and PRC2 to the promoter of E-cadherin and thus inhibited the expression of E-cadherin, promoting EMT and inducing invasion and metastasis of CRC.
CONCLUSION: Our study reveals that Snail2 might epigenetically suppress the expression of E-cadherin during CRC metastasis.

Wongjampa W, Ekalaksananan T, Chopjitt P, et al.
Suppression of miR-22, a tumor suppressor in cervical cancer, by human papillomavirus 16 E6 via a p53/miR-22/HDAC6 pathway.
PLoS One. 2018; 13(10):e0206644 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs that function to down-regulate gene expression involving in various cellular processes related to carcinogenesis. Recently, miR-22 was identified as a tumor-suppressing miRNA in many human cancers. However, the regulatory mechanism and the specific function of this miRNA in cervical cancer remain unclear. In the present study, we carried out gene transfection, western blot and quantitative RT-PCR to explore the regulatory mechanism and the functional role of miR-22 in cervical cancer. We verified that miR-22 was down-regulated in cervical cancer tissues and cervical cancer cell lines relative to matched non-tumor tissues and normal human cervical keratinocyte line (HCK1T). By contrast, histone deacetylase 6 (HDAC6) was inversely correlated with miR-22 in both cervical tissues and cancer cell lines. Mechanically, HDAC6 was down-regulated by miR-22 at the post-transcriptional level, via a specific target site within the 3'UTR, identified by a luciferase reporter assay. Moreover, we also showed that the correlation between miR-22 and HDAC6 expression was regulated by an E6/p53 pathway in HCK1Ts expressing HPV16 E6. For functional study, an ectopic expression of miR-22 could inhibit cell proliferation and migration, and could induce apoptosis of cervical cancer cell lines. These findings demonstrated that miR-22 was down-regulated in cervical cancer and inversely collated with its downstream target HDAC6. MiR-22 acts as tumor suppressor by inhibiting proliferation and migration, and by inducing apoptosis of cervical cancer cell lines by targeting the 3'UTR of HDAC6. This newly identified E6/p53/miR-22/HDAC6 regulatory network might be a candidate therapeutic target for cervical cancer.

Yang F, Wang F, Liu Y, et al.
Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative breast cancer cells.
Life Sci. 2018; 213:149-157 [PubMed] Related Publications
AIMS: To study the underlying mechanisms of sulforaphane, a natural histone deacetylase (HDAC) inhibitor, in inhibiting triple negative breast cancer cells growth and the therapeutic effects of combination of sulforaphane and doxorubicin in TNBC treatment.
MATERIALS AND METHODS: The antineoplastic activity of sulforaphane was evaluated in MDA-MB-231, BT549 and MDA-MB-468 cells with MTT assay. Cell apoptosis was detected with Annexin V/PI double staining by Flow cytometry. Cell autophagy was detected with fluorescence microscope. The effects of Sulforaphane and Doxorubicin combination treatments on cells growth were determined with Chou-Talalay median effect/combination index (CI) model. mRNA and protein expression of genes were assayed respectively with real-time PCR and Western bloting. Protein-protein interaction was detected with co-immunoprecipation. Gene knock-down was performed with small interfere RNA. In vivo assay of combinational treatment with sulforaphane and doxorubicin was investigated in athymic nude mice bearing MDA-MB-231 xenografts.
KEY FINDINGS: Results showed that sulforaphane inhibited cell growth and induced autophagy in MDA-MB-231, BT549 and MDA-MB-468 cells. Further study demonstrated that sulforaphane induced autophagy by down-regulating expression of HDAC6, which resulted in increased membrane translocation and acetylation modification of phosphatase and tensin homolog (PTEN). Sulforaphane and doxorubicin combination exhibited a synergistic inhibition on TNBC cells growth. In nude mice, the combination of sulforaphane and doxorubicin displayed a greater inhibitory effect on MDA-MB-231 xenografts growth as compared to either treatment alone.
SIGNIFICANCE: Our study suggested that induction of autophagy by targeting HDAC6 in combination with chemotherapeutic reagent may provide a novel strategy for TNBC therapy.

Cheng M, Cai W, Huang W, et al.
Histone deacetylase 6 regulated expression of IL-8 is involved in the doxorubicin (Dox) resistance of osteosarcoma cells via modulating ABCB1 transcription.
Eur J Pharmacol. 2018; 840:1-8 [PubMed] Related Publications
Emerging evidence shows that cytokines such as interleukins (ILs) are involved in the progression and chemoresistance of multiple tumors, including osteosarcoma (OS). Our present study established the doxorubicin (Dox) resistant human OS MG-63 and HOS cells and named them MG-63/Dox and HOS/Dox, respectively. The expression of IL-8, while not VEGFA, IL-32, or IL-34, was significantly increased in OS/Dox cells as compared with that in the parental cells. IL-8 neutralization antibody can significantly increase the Dox sensitivity of OS/Dox cells. Further, IL-8 can up regulate ABCB1, which encodes one important ATP-binding cassette (ABC) transporter /P-glycoprotein (P-gp). Mechanically, IL-8 increased the transcription of ABCB1 via up regulating its promoter activity, while had no effect on its protein or mRNA stability. Targeted inhibition of p65 can attenuate IL-8 induced transcription of ABCB1 in OS cells. Treatment OS cells with 5-aza-dC, the inhibitor of DNMT, had no effect on expression of IL-8. Expression of HDAC6 in MG-63/Dox and HOS/Dox cells was significantly greater than that in their parental cells. Knockdown of HDAC6 can suppress the expression of IL-8 in OS cells. Collectively, our data showed that HDAC6 mediated upregulation of IL-8 can regulate the Dox sensitivity of OS cells via transcriptionally regulating the expression of ABCB1. Targeted inhibition of IL-8 might be a potent potential approach for overcome the Dox resistance of OS cells and helpful for clinical therapy of OS patients.

Sudo H
Microtubule Hyperacetylation Enhances KL1-Dependent Micronucleation under a Tau Deficiency in Mammary Epithelial Cells.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
Enhanced microtubule acetylation has been identified as a negative prognostic indicator in breast cancer. We reported previously that primary cultured human mammary epithelial cells manifest breast cancer-related aneuploidization via the activation of severing protein katanin-like (KL)1 when tau is deficient. To address in this current study whether microtubule hyperacetylation is involved in breast carcinogenesis through mitosis, the effects of tubacin on human mammary epithelial cells were tested using immunofluorescence techniques. Tau-knockdown cells showed enhancement of KL1-dependent events, chromosome-bridging and micronucleation in response to tubacin. These enhancements were suppressed by further expression of an acetylation-deficient tubulin mutant. Consistently, using a rat fibroblast-based microtubule sensitivity test, it was confirmed that KL1 also shows enhanced activity in response to microtubule hyperacetylation as well as katanin. It was further observed in rat fibroblasts that exogenously expressed KL1 results in more micronucleation under microtubule hyperacetylation conditions. These data suggest that microtubule acetylation upregulates KL1 and induces more aneuploidy if tau is deficient. It is thus plausible that microtubule hyperacetylation promotes tumor progression by enhancing microtubule sensitivity to KL1, thereby disrupting spindle microtubules and this process could be reversed by the microtubule-binding and microtubule protective octapeptide NAPVSIPQ (NAP) which recruits tau to the microtubules.

Cosenza M, Pozzi S
The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease.
Int J Mol Sci. 2018; 19(8) [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.

Caumanns JJ, Wisman GBA, Berns K, et al.
ARID1A mutant ovarian clear cell carcinoma: A clear target for synthetic lethal strategies.
Biochim Biophys Acta Rev Cancer. 2018; 1870(2):176-184 [PubMed] Related Publications
SWI/SNF chromatin remodeling complexes play an important role in the epigenetic regulation of chromatin structure and gene transcription. Mutual exclusive subunits in the SWI/SNF complex include the DNA targeting members ARID1A and ARID1B as well as the ATPases SMARCA2 and SMARCA4. SWI/SNF complexes are mutated across many cancer types. The highest mutation incidence is found in ARID1A, primarily consisting of deleterious mutations. Current advances have reported synthetic lethal interactions with the loss of ARID1A in several cancer types. In this review, we discuss targets that are only important for tumor growth in an ARID1A mutant context. We focus on synthetic lethal strategies with ARID1A loss in ovarian clear cell carcinoma, a cancer with the highest ARID1A mutation incidence (46-57%). ARID1A directed lethal strategies that can be exploited clinically include targeting of the DNA repair proteins PARP and ATR, and the epigenetic factors EZH2, HDAC2, HDAC6 and BRD2.

Sun N, Wang CY, Sun YQ, et al.
Down-regulated miR-148b increases resistance to CHOP in diffuse large B-cell lymphoma cells by rescuing Ezrin.
Biomed Pharmacother. 2018; 106:267-274 [PubMed] Related Publications
BACKGROUND: Aberrant microRNA (miRNAs) have recently been proposed as important regulators in acquiring resistance to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to establish the role of miR-148b in the development of CHOP resistance in DLBCL.
METHODS: The expression patterns of miR-148b, HDAC6, and Ezrin were detected in CHOP-resistant clinical specimens and a DLBCL cell line. miR-148b, HDAC6, and Ezrin in DLBCL cells were manipulated by cell transfection to explore the functional correlation between them. Cell viability was determined using a CCK-8 assay.
RESULTS: We found that miR-148b levels were markedly reduced and that the protein expressions of HDAC6 and Ezrin were increased in DLBCL CHOP-resistant clinical specimens and the cell line CRL2631/CHOP. Indeed, HDAC6 decreased the acetylation of histones H3 and H4 in the miR-148b promoter to inhibit miR-148b expression in DLBCL. Moreover, down-regulated miR-148b encouraged CHOP resistance in CRL2631 cells and miR-148b sensitized CRL2631 cells. We further revealed that Ezrin was negatively regulated by miR-148b and that the knockdown of Ezrin significantly attenuated CHOP resistance in CRL2631 cells induced by miR-148b silencing. MiR-148b also sensitized CRL2631/CHOP cell xenografts to CHOP in mice.
CONCLUSION: Our data indicated that the high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.

Liu Y, Li Y, Liu S, et al.
NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model.
Cancer Res. 2018; 78(13):3709-3717 [PubMed] Free Access to Full Article Related Publications
Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line-derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.

Lee DH, Won HR, Ryu HW, et al.
The HDAC6 inhibitor ACY‑1215 enhances the anticancer activity of oxaliplatin in colorectal cancer cells.
Int J Oncol. 2018; 53(2):844-854 [PubMed] Related Publications
ACY‑1215, also known as ricolinostat, is a leading histone deacetylase 6 inhibitor, which is currently being tested in clinical trials for hematological malignancies. Previous studies have reported that ACY‑1215 is not potent enough as a monotherapy for the treatment of colorectal cancer (CRC), which generally requires combination therapy for successful treatment. Therefore, the present study aimed to determine whether the synergistic interaction detected between ACY‑1215 and anticancer agents in hematological cancers could occur in solid tumors. The results of the present study indicated that ACY‑1215 exerted a potent synergistic anti-proliferative effect when used in combination with anticancer agents in CRC cells. The combination of ACY‑1215 and oxaliplatin was more potent than either drug alone, as indicated by an increase in apoptotic cells and their effects on the apoptotic pathway; ACY‑1215 and oxaliplatin cotreatment activated caspase‑3 and poly (ADP ribose) polymerase, increased B‑cell lymphoma (Bcl)‑2 homologous antagonist/killer expression, and decreased Bcl‑extra large protein, phosphorylated-extracellular signal-regulated kinase and phosphorylated-protein kinase B expression. In addition, combined treatment of ACY‑1215 and anticancer agents induced synergistic upregulation of programmed death‑ligand 1. These findings suggested that a therapeutic strategy that combines ACY‑1215 and oxaliplatin warrants attention for the treatment of solid tumors, including CRC.

Vanaja GR, Ramulu HG, Kalle AM
Overexpressed HDAC8 in cervical cancer cells shows functional redundancy of tubulin deacetylation with HDAC6.
Cell Commun Signal. 2018; 16(1):20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Histone deacetylases (HDACs) are involved in epigenetic gene regulation via deacetylation of acetylated lysine residues of both histone and non-histone proteins. Among the 18 HDACs identified in humans, HDAC8, a class I HDAC, is best understood structurally and enzymatically. However, its precise subcellular location, function in normal cellular physiology, its protein partners and substrates still remain elusive.
METHODS: The subcellular localization of HDAC8 was studied using immunofluorescence and confocal imaging. The binding parterns were identified employing immunoprecipitation (IP) followed by MALDI-TOF analysis and confirmed using in-silico protein-protein interaction studies, HPLC-based in vitro deacetylation assay, intrinsic fluorescence spectrophotometric analysis, Circular dichroism (CD) and Surface Plasmon Resonance (SPR). Functional characterization of the binding was carried out using immunoblot and knockdown by siRNA. Using one way ANOVA statistical significance (n = 3) was determined.
RESULTS: Here, we show that HDAC8 and its phosphorylated form (pHDAC8) localized predominantly in the cytoplasm in cancerous, HeLa, and non-cancerous (normal), HEK293T, cells, although nucleolar localization was observed in HeLa cells. The study identified Alpha tubulin as a novel interacting partner of HDAC8. Further, the results indicated binding and deacetylation of tubulin at ac-lys40 by HDAC8. Knockdown of HDAC8 by siRNA, inhibition of HDAC8 and/or HDAC6 by PCI-34051 and tubastatin respectively, cell-migration, cell morphology and cell cycle analysis clearly explained HDAC8 as tubulin deacetylase in HeLa cells and HDAC6 in HEK 293 T cells.
CONCLUSIONS: HDAC8 shows functional redundancy with HDAC6 when overexpressed in cervical cancer cells, HeLa, and deacetylaes ac-lys40 of alpha tubulin leading to cervical cancer proliferation and progression.

Tao H, Chen YY, Sun ZW, et al.
Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90.
J Cell Biochem. 2018; 119(8):6623-6632 [PubMed] Free Access to Full Article Related Publications
Esophageal carcinoma is aggressive in nature and its prognosis is largely dependent on the degree of invasion. Histone deacetylase 6 (HDAC6), as the most unique member of HDACs family, has the positive activity to promote initiation and progression of various cancers via targeting multiple non-histone proteins in cytoplasm. In this study, we found that HDAC6 was over-expressed in three esophageal cancer cell lines (KYSE140, KYSE170, KYSE180) when compared to non-carcinoma esophageal epithelial cell HEEC-1. Then two HDAC6 specific siRNAs and HDAC6 inhibitor tubastatin A greatly suppressed KYSE140 and KYSE180 cells proliferation and migration, and the inhibition of cell motility was accompanied by elevated acetylation of α-tubulin, a target of HDAC6. Consistently, the microtubulin skeleton was stabilized after HDAC6 knockdown or inhibition. In addition, acetylation status of HSP90, another HDAC6 target, was also increased towards HDAC6 knockdown or inhibition by co-immunoprecipitation assay. Besides, co-treatment of HSP90 inhibitor (PU-H71) and HDAC6 inhibitor (tubastatin A) induced a stronger cell migration inhibition compared to administration of either drug alone. Furthermore, cell proliferation of KYSE140 and KYSE180 were also compromised in response to combination of HDAC6 and HSP90 inhibitors. Additionally, co-administration of HSP90 inhibitor and HDAC6 inhibitor strongly inhibited tumor growth in vivo. Taken together, our results indicated that HDAC6 is a promising target by inhibiting HSP90 function in ESCC.

Pinazza M, Ghisi M, Minuzzo S, et al.
Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells.
Oncogene. 2018; 37(28):3839-3851 [PubMed] Free Access to Full Article Related Publications
Several studies have revealed that endosomal sorting controls the steady-state levels of Notch at the cell surface in normal cells and prevents its inappropriate activation in the absence of ligands. However, whether this highly dynamic physiologic process can be exploited to counteract dysregulated Notch signaling in cancer cells remains unknown. T-ALL is a malignancy characterized by aberrant Notch signaling, sustained by activating mutations in Notch1 as well as overexpression of Notch3, a Notch paralog physiologically subjected to lysosome-dependent degradation in human cancer cells. Here we show that treatment with the pan-HDAC inhibitor Trichostatin A (TSA) strongly decreases Notch3 full-length protein levels in T-ALL cell lines and primary human T-ALL cells xenografted in mice without substantially reducing NOTCH3 mRNA levels. Moreover, TSA markedly reduced the levels of Notch target genes, including pTα, CR2, and DTX-1, and induced apoptosis of T-ALL cells. We further observed that Notch3 was post-translationally regulated following TSA treatment, with reduced Notch3 surface levels and increased accumulation of Notch3 protein in the lysosomal compartment. Surface Notch3 levels were rescued by inhibition of dynein with ciliobrevin D. Pharmacologic studies with HDAC1, 6, and 8-specific inhibitors disclosed that these effects were largely due to inhibition of HDAC6 in T-ALL cells. HDAC6 silencing by specific shRNA was followed by reduced Notch3 expression and increased apoptosis of T-ALL cells. Finally, HDAC6 silencing impaired leukemia outgrowth in mice, associated with reduction of Notch3 full-length protein in vivo. These results connect HDAC6 activity to regulation of total and surface Notch3 levels and suggest HDAC6 as a potential novel therapeutic target to lower Notch signaling in T-ALL and other Notch3-addicted tumors.

Wang F, Zheng L, Yi Y, et al.
SKLB-23bb, A HDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules.
Mol Cancer Ther. 2018; 17(4):763-775 [PubMed] Related Publications
Our previous study reported that SKLB-23bb, an orally bioavailable HDAC6-selective inhibitor, exhibited superior antitumor efficiency both

Li X, Peterson YK, Inks ES, et al.
Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status.
J Med Chem. 2018; 61(6):2589-2603 [PubMed] Free Access to Full Article Related Publications
Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC

Bae J, Hideshima T, Tai YT, et al.
Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
Leukemia. 2018; 32(9):1932-1947 [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138

Forsythe N, Refaat A, Javadi A, et al.
The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic
Mol Cancer Ther. 2018; 17(6):1280-1290 [PubMed] Free Access to Full Article Related Publications

Dom M, Offner F, Vanden Berghe W, Van Ostade X
Proteomic characterization of Withaferin A-targeted protein networks for the treatment of monoclonal myeloma gammopathies.
J Proteomics. 2018; 179:17-29 [PubMed] Related Publications
Withaferin A (WA), a natural steroid lactone from the plant Withania somnifera, is often studied because of its antitumor properties. Although many in vitro and in vivo studies have been performed, the identification of Withaferin A protein targets and its mechanism of antitumor action remain incomplete. We used quantitative chemoproteomics and differential protein expression analysis to characterize the WA antitumor effects on a multiple myeloma cell model. Identified relevant targets were further validated by Ingenuity Pathway Analysis and Western blot and indicate that WA targets protein networks that are specific for monoclonal gammopathy of undetermined significance (MGUS) and other closely related disorders, such as multiple myeloma (MM) and Waldenström macroglobulinemia (WM). By blocking the PSMB10 proteasome subunit, downregulation of ANXA4, potential association with HDAC6 and upregulation of HMOX1, WA puts a massive blockage on both proteotoxic and oxidative stress responses pathways, leaving cancer cells defenseless against WA induced stresses. These results indicate that WA mediated apoptosis is preceded by simultaneous targeting of cellular stress response pathways like proteasome degradation, autophagy and unfolded protein stress response and thus suggests that WA can be used as an effective treatment for MGUS and other closely related disorders.
SIGNIFICANCE: Multifunctional antitumor compounds are of great potential since they reduce the risk of multidrug resistance in chemotherapy. Unfortunately, characterization of all protein targets of a multifunctional compound is lacking. Therefore, we optimized an SILAC quantitative chemoproteomics workflow to identify the potential protein targets of Withaferin A (WA), a natural multifunctional compound with promising antitumor properties. To further understand the antitumor mechanisms of WA, we performed a differential protein expression analysis and combined the altered expression data with chemoproteome WA target data in the highly curated Ingenuity Pathway database. We provide a first global overview on how WA kills multiple myeloma cancer cells and serve as a starting point for further in depth experiments. Furthermore, the combined approach can be used for other types of cancer and/or other promising multifunctional compounds, thereby increasing the potential development of new antitumor therapies.

Song YW, Lim Y, Cho SK
2,4‑Di‑tert‑butylphenol, a potential HDAC6 inhibitor, induces senescence and mitotic catastrophe in human gastric adenocarcinoma AGS cells.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(5):675-683 [PubMed] Related Publications
The natural product 2,4‑di‑tert‑butylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased β‑galactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity. In silico docking analysis showed that DTBP docked at the entrance of the ligand-binding pocket of the HDAC6 enzyme. Accordingly, DTBP represents a promising lead structure for the development of HDAC6 inhibitors, with an improvement in specificity conferred by modification of the cap group. We propose for the first time that the underlying mechanism of the anticancer activity of DTBP is attributed to inhibition of HDAC6 activity.

Mansini AP, Lorenzo Pisarello MJ, Thelen KM, et al.
MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma.
Hepatology. 2018; 68(2):561-573 [PubMed] Free Access to Full Article Related Publications
Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a posttranscriptional regulation, possibly involving microRNAs (miRNAs). Here, we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are down-regulated in CCA both in vitro and in vivo. Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, short hairpin RNA (shRNA) depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia.
CONCLUSION: These data suggest that down-regulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. (Hepatology 2018).

Niu Y, Jin Y, Deng SC, et al.
MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer.
Oncogene. 2018; 37(13):1743-1758 [PubMed] Related Publications
Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.

Liu J, Luan W, Zhang Y, et al.
HDAC6 interacts with PTPN1 to enhance melanoma cells progression.
Biochem Biophys Res Commun. 2018; 495(4):2630-2636 [PubMed] Related Publications
Histone deacetylase 6 (HDAC6) plays an important role in oncogenic transformation and cancer metastasis. Our previous study has demonstrated that HDAC6 was highly expressed in melanoma cells, and contributed to the proliferation and metastasis of melanoma cells. However, the underlying mechanism of HDAC6 in melanoma metastasis and progression remains largely unclear. In this study, we reported that HDAC6 directly interacted with Tyrosine-protein phosphatase non-receptor type 1 (PTPN1) by performing co-immunoprecipitation (Co-IP) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS). HDAC6 increased the protein level of PTPN1 independent of histone modifying activity. In addition, PTPN1 promoted proliferation, colony formation and migration while decreased apoptosis of melanoma cells through activating extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, we found that matrix metallopeptidase 9 (MMP9) was increased by HDAC6/PTPN1/ERK1/2 axis, which might serve as a mechanism for melanoma invasion and metastasis. In conclusion, HDAC6 might enhance aggressive melanoma cells progression via interacting with PTPN1, which was independent of its histone modifying activity.

Ingallina E, Sorrentino G, Bertolio R, et al.
Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis.
Nat Cell Biol. 2018; 20(1):28-35 [PubMed] Free Access to Full Article Related Publications
Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function)

Yang W, Liu Y, Gao R, et al.
HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway.
Cancer Lett. 2018; 415:164-176 [PubMed] Related Publications
The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on stemness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSCs comparing to non-stem tumor cells. Inhibiting HDAC6 downregulated glioma-associated oncogene homolog 1 (Gli1), Patched (Ptch1 and Ptch2) receptors, components of SHH signal, expression and activity in GSCs. Restraining HDAC6 decreased cell proliferation, induces differentiation and increased apoptosis of GSCs via inactivation of SHH/Gli1 signaling pathway. Moreover, HDAC6 inhibition decreased DNA damage repair capacity of GSCs through degradation of checkpoint kinase (CHK) 1 caused by X-linked inhibitor of apoptosis (XIAP) downregulation, leading to elevated radiosensitivity. Taken together, these findings indicate that HDAC6 inhibition decreased stemness of GSCs and enhanced GSCs radiosensitivity through inactivating SHH/Gli1 pathway. This provides a promising novel drug target to overcome GSCs stemness and radioresistance.

Yao ZG, Li WH, Hua F, et al.
LBH589 Inhibits Glioblastoma Growth and Angiogenesis Through Suppression of HIF-1α Expression.
J Neuropathol Exp Neurol. 2017; 76(12):1000-1007 [PubMed] Related Publications
Glioblastoma (GBM) is an angiogenic malignancy with a highly unfavorable prognosis. Angiogenesis in GBM represents an adaptation to a hypoxic microenvironment and is correlated with tumor growth, invasion, clinical recurrence, and lethality. LBH589 (also called panobinostat) is a histone deacetylase (HDAC) inhibitor with potent antitumor activity. In the current study, we investigated the mechanism and effects of LBH589 on GBM growth and hypoxia-induced angiogenesis in vitro and in vivo. To determine the antitumor and angiogenesis activity and mechanism of LBH589, we used cell proliferations in vitro and GBM xenografts in vivo. To clarify mechanisms of LBH589 on angiogenesis, HDAC assay, RT-PCR, Western blot, and co-immunoprecipitation assays were performed. We found LBH589 displayed significant antitumor effects on GBM as demonstrated by inhibited cell proliferation, slower tumor growth, and decreased microvessel density of subcutaneous xenografts. These actions of LBH589 resulted from the disruption of heat shock protein 90/HDAC6 complex, increased HIF-1α instability and degradation, and decreased VEGF expression. Our results indicate the potential antiangiogenic activity of LBH589 in human GBM and provide some preclinical data to warrant further exploration of HDAC inhibitors for the treatment of advanced glioma. Moreover, our study supports the role of HDAC inhibitors as a therapeutic strategy to target tumor angiogenesis.

Jia YJ, Liu ZB, Wang WG, et al.
HDAC6 regulates microRNA-27b that suppresses proliferation, promotes apoptosis and target MET in diffuse large B-cell lymphoma.
Leukemia. 2018; 32(3):703-711 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Histone deacetylase 6 (HDAC6) is frequently altered in DLBCL and inhibition of HDAC6 has potent anti-tumor effects in vitro and in vivo. We profiled miRNAs that altered in the HDAC6 knockdown DLBCL cells with NanoString nCounter assay and identified microRNA-27b (miR-27b) as the most significantly increased miRNA. We validated decreased expression of miR-27b in DLBCL tissues, and we found that low expression of miR-27b was associated with poor overall survival of patients with DLBCL. In addition, forced expression of miR-27b suppressed DLBCL cell viability and proliferation in vitro, and inhibited tumor growth in vivo. Mechanistically, Rel A/p65 is found to negatively regulate miR-27b expression, and its acetylation and block of nuclear translocalization caused by HDAC6 inhibition significantly elevates miR-27b expression. Furthermore, miR-27b targets MET and thus represses the MET/PI3K/AKT pathway. These findings highlight an important role of miR-27b in the development of DLBCL and uncover a HDAC6-Rel A/p65-miR-27b-MET signaling pathway. Elevating miR-27b through HDAC6 inhibition would be a promising strategy for DLBCL treatment.

Zhang G, Gan YH
Synergistic antitumor effects of the combined treatment with an HDAC6 inhibitor and a COX-2 inhibitor through activation of PTEN.
Oncol Rep. 2017; 38(5):2657-2666 [PubMed] Free Access to Full Article Related Publications
Chemotherapy is one of the most effective non-surgical treatments for various types of tumor. Identifying different combinations of antitumor agents that can produce synergistic antitumor effects remains an important clinical strategy. In the present study, we showed that the combination of histone deacetylase 6 (HDAC6) inhibitor tubastatin A together with cyclooxygenase-2 (COX-2) inhibitor celecoxib resulted in synergistic antitumor effects in CAL 27 and SACC-83 cells. Treatment with celecoxib alone promoted the membrane translocation of phosphatase and tensin homolog (PTEN), indicating PTEN activation, and consequently led to protein kinase B (AKT) dephosphorylation (inactivation). Similarly, treatment with an HDAC6 inhibitor alone promoted PTEN membrane translocation and correspondingly dephosphorylated AKT. The combination of celecoxib and an HDAC6 inhibitor synergistically increased PTEN membrane translocation and inactivated AKT. Moreover, celecoxib enhanced the HDAC6 inhibitor-induced antitumor effects in PTEN-deficient U-87 MG cells that had been stably transfected with wild-type PTEN, but not in the same cell line stably transfected with mutant PTEN-K163R, which cannot be activated by HDAC6 inhibitors. In summary, the results indicated that the COX-2 inhibitor celecoxib enhanced the HDAC6 inhibitor-induced antitumor effects by activating the PTEN/AKT signaling pathway.

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