HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma

Wang, Wenwen; Tang, Fang; Hu, Pengchao; Wang, Ying; Gong, Jun; Sun, Shaoxing; Xie, Conghua

doi:10.3892/or.2016.4811

Cited by 48 publications

(37 citation statements)

References 32 publications

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“…6). In comparison 36 , observed an increased expression of HDAC6 in lung AdCa and the aberrant expression correlated negatively with patient prognosis. Recently, it has also been reported that HDAC6 suppresses RASSF1A expression 37 .…”

Section: Discussionmentioning

confidence: 81%

Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

Kiehl

Zimmermann

Savai

et al. 2017

Sci Rep

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Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methylation compared to normal cells. The functional annotation of hypermethylated CGI revealed that the hypermethylation was associated with homeobox domain genes and targets marked by repressive histone modifications. The strongest methylation variation was observed in transitional areas of CGI, termed shores. 5′-shores of promoter-associated CGI in lung cancer cell lines were higher methylated than 3′-shores. Within two tandem-oriented genes, a significant hypermethylation of the downstream-located CGI promoters was revealed. Hypermethylation correlates with the length of the intergenic region between such tandem genes. As the RASSF1A tumor suppressor gene represents such a downstream tandem gene, its silencing was analyzed using an inducible system. It was determined that the induction of an upstream gene led to a repression of RASSF1A through a process involving histone deacetylases and CPSF1. A tumor-specific increase in expression of histone deacetylases and CPSF1 was detected in lung cancer. Our results suggest that the downstream gene could be susceptible to epigenetic silencing when organized in a tandem orientation.

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Section: Discussionmentioning

confidence: 81%

Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

Kiehl

Zimmermann

Savai

et al. 2017

Sci Rep

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“…We used the HDAC3-specific inhibitor RGFP96622, HDAC6-specific inhibitor CAY1060323, and HDAC8-specific inhibitor PCI3405124 to treat expanded NK cells. We found that VPA ≤ 0.5 mM, RGFP966 ≤ 20 μM, CAY10603 ≤ 50 nM and PCI34051 ≤ 0.625 μM did not impair NK cell viability at 24 h (Suppl.…”

Section: Resultsmentioning

confidence: 99%

The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3

Wang

Yao

et al. 2017

Sci Rep

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NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation. In this study, we investigated regulation of NKG2D expression in NK cells by VPA and entinostat by assessing protein expression, phosphorylation, and interaction of HDACs and STAT3. We find that VPA selectively inhibits STAT3 tyrosine705 phosphorylation, but entinostat does not. STAT3 complexes with HDAC3, and HDAC3 inhibition represses STAT3 phosphorylation and therefore NKG2D expression. NK cells from STAT3 wild-type mice downregulate NKG2D in response to VPA, but not NK cells from STAT3 knockout mice. These results show that VPA is a potent inhibitor of STAT3 phosphorylation and demonstrate that histone acetylation and STAT3 tyrosine705 phosphorylation cooperate in regulating NKG2D expression in NK cells.

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“…It was found to be upregulated in oral squamous cell carcinoma, 26 ovarian carcinoma, 27,28 and primary acute myeloid leukemia 29 relative to nonmalignant controls. Preclinical studies have demonstrated that HDAC6 inhibitors display antitumor activity when used either alone or in combination with other agents to treat multiple myeloma, 30,31 B-cell lymphoma, 24,32 breast cancer, 33,34 lung cancer, 35,36 and melanoma. 37,38 At present, HDAC6-selective inhibitors are in clinical trials to treat several solid tumor types, multiple myeloma, and lymphoma (registered at www.clinicaltrials.…”

Section: Introductionmentioning

confidence: 99%

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia

et al. 2018

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Although the treatment paradigm for chronic lymphocytic leukemia (CLL) is rapidly changing, the disease remains incurable, except with allogeneic bone marrow transplantation, and resistance, relapsed disease, and partial responses persist as significant challenges. Recent studies have uncovered roles for epigenetic modification in the regulation of mechanisms contributing to malignant progression of CLL B cells. However, the extent to which epigenetic modifiers can be targeted for therapeutic benefit in CLL patients remains poorly explored. We report for the first time that expression of epigenetic modifier histone deacetylase 6 (HDAC6) is upregulated in CLL patient samples, cell lines, and euTCL1 transgenic mouse models compared with HDAC6 in normal controls. Genetic silencing of HDAC6 conferred survival benefit in euTCL1 mice. Administration of isoform-specific HDAC6 inhibitor ACY738 in the euTCL1 aging and adoptive transfer models deterred proliferation of CLL B cells, delayed disease onset via disruption of B-cell receptor signaling, and sensitized CLL B cells to apoptosis. Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition.

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HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma

Cited by 48 publications

References 32 publications

Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia

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