HDAC10 as a potential therapeutic target in ovarian cancer

Abstract

Objective We analyzed histone deacetylase 10 (HDAC10) for function in the context of the DNA damage response in BRCA1-null ovarian cancer cells as well as evaluated the potential of general HDAC inhibitors in primary ovarian carcinoma cells. HDAC10 had previously been shown to be highly stimulatory to the process of homology directed repair in HeLa cells, and in this study we investigated whether HDAC10 could impact in vitro the response to anticancer therapies. We hypothesized that the loss of HDAC10 would sensitize cells to platinum therapy. Methods We combined informatics analysis of large DNA sequencing datasets from ovarian cancer tumors with tissue culture based assays of primary and established cell lines to test for sensitivity to platinum therapy if HDAC10 activity was inhibited or depleted. Results Using The Cancer Genome Atlas (TCGA) dataset, we found that deep deletions in HDAC10 occurred in 5–10% of ovarian cancer tumors. From the TCGA data we found that low HDAC10 mRNA levels correlated with platinum sensitivity of the tumors. Cell proliferation and DNA damage assays in a BRCA1-null ovarian carcinoma cell line demonstrated reduced DNA repair capacity and sensitization of platinum therapy. Similarly, primary ovarian carcinoma cells demonstrated a sensitization to platinum therapies when treated with HDAC inhibitors. Conclusions From the results of this study, we suggest that the inhibition of HDAC10 may potentiate the effects of platinum therapies in ovarian tumors.

Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

“…The hydroxamic analogue 10 showed lower selectivity for HDACs 1–3 over HDACs 6 and 8 (Table ), whereas the mercaptosulfide analogue 12 maintained such selectivity but showed the strongest potency against HDAC10 (IC 50 =3.6 n m ), being 10‐ to 25‐fold more active toward this isoform with respect to HDACs 1–3. These results confirmed the importance of the ZBG in the modulation of HDAC inhibitory activity and selectivity profile, and provided some hints about how to address selectivity toward HDAC10, which recently showed to promote lung cancer proliferation and was found to be a potential therapeutic target for ovarian cancer …”

“…These results confirmedt he importance of the ZBG in the modulation of HDAC inhibitory activity and ChemMedChem 2017ChemMedChem , 12,1917ChemMedChem -1926 www.chemmedchem.org selectivity profile, and provided some hints about how to address selectivityt owardH DAC10, which recently showedt o promote lung cancerp roliferation and was found to be ap otential therapeutic target for ovarian cancer. [24,25] Finally,t he disulfide analogues reported by the same research group highlighted that, by changing the prodrug form of largazole thiol it was possible to modulate the ligands ADME profile, particularlya sr egards the onset of action and oral bioavailability,a ss hown by in vivo histoneh yperacetylation assays in HCT116 cells andm ouse xenograft models. [26] Analogues with modifiedv aline unit…”

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

“…In neuroblastoma, the polyamine regulating ODC1 was found co-upregulated with MYCN and correlates with poor outcome in neuroblastoma, suggesting a detrimental role in neuroblastoma biology (Gamble et al 2012; Hogarty et al 2008; Lastowska et al 2007). Moreover, polyamines are known to modulate DNA conformation by strongly binding to the DNA helix (Feuerstein et al 1990; Matthews 1993), and recently identified roles of HDAC10 include regulation of DNA mismatch and DSB repair in various cancer types such as ovarian carcinoma (Islam et al 2017; Radhakrishnan et al 2015). DNA damage has also been described as a result of HDAC6 depletion and inhibition (Namdar et al 2010; Wang et al 2012), and the above-mentioned HDAC8-dependent cohesin complex is well known to accumulate at DNA break sites to mediate DNA repair and recruit cell cycle checkpoint-activating proteins (Caron et al 2012; Watrin and Peters 2009).…”

HDAC10 expression is associated with DNA mismatch repair gene and is a predictor of good prognosis in colon carcinoma

“…HDAC10 was demonstrated to be a tumor suppresser in some types of cancer, including clear cell renal cell carcinoma (13), cervical cancer (19), gastric cancer (12,20), and ovarian cancer (16). The function of HDAC10 in lung cancer is a matter of debate (10,15).…”

“…HDAC10 has been reported to be involved in homologous recombination (3), melanogenesis (4), cells autophagy (5-7), cell cycle regulation (8), DNA mismatch repair (9) and cancer progression (10)(11)(12)(13)(14)(15)(16). While HDAC10 was reported to suppresses the proliferation and invasion of clear cell renal cell carcinoma (13), it was also demonstrated to promote cell proliferation via AKT phosphorylation in lung cancer (15).…”