HDAC6 Degradation Inhibits the Growth of High-Grade Serous Ovarian Cancer Cells

SIMPLE SUMMARY: The objective of this study was, firstly, to investigate the relationship between Histone deacetylase 6 (HDAC6) expression and survival in patients with ovarian cancer and, secondly, to test the effects of histone deacetylase 6 (HDAC6) inhibition on ovarian cancer cells in vitro. A meta-analysis of the correlation between HDAC6 gene expression and survival was performed on 3573 ovarian tumors from 19 datasets showed that high HDAC6 gene expression was associated with a decreased risk of death. Knockdown of HDAC6 gene expression with small interfering RNA (siRNA) and protein expression with a HDAC6 targeting protein degrader decreased ovarian cell proliferation, migration, and viability. Conversely, the selective inhibition of HDAC6 catalytic activity did not produce a robust inhibition of HDAC6 protein function. In summary, we demonstrated, for the first time, that HDAC6 over-expression in ovarian cancers is a favorable prognostic marker. We provide evidence to suggest that inhibition of HDAC6 catalytic activity has limited efficacy as a monotherapy in ovarian cancers. ABSTRACT: Histone deacetylase 6 (HDAC6) is a unique histone deacetylating enzyme that resides in the cell cytoplasm and is linked to the modulation of several key cancer related responses, including cell proliferation and migration. The promising anti-cancer response of the first-generation HDAC6 catalytic inhibitors continues to be assessed in clinical trials, although its role in high grade serous ovarian cancer is unclear. This study investigated HDAC6 tumor expression by immunohistochemistry in high-grade serous ovarian cancer (HGSOC) tissue samples and a meta-analysis of HDAC6 gene expression in ovarian cancer from publicly available data. The pharmacological activity of HDAC6 inhibition was assessed in a patient-derived model of HGSOC. HDAC6 was found to be highly expressed in HGSOC tissue samples and in the patient-derived HGSOC cell lines where higher HDAC6 protein and gene expression was associated with a decreased risk of death (hazard ratio (HR) 0.38, (95% confidence interval (CI), 0.16–0.88; p = 0.02); HR = 0.88 (95% CI, 0.78–0.99; p = 0.04)). Similarly, the multivariate analysis of HDAC6 protein expression, adjusting for stage, grade, and cytoreduction/cytoreductive surgery was associated with a decreased risk of death (HR = 0.19 (95% CI, 0.06–0.55); p = 0.002). Knock-down of HDAC6 gene expression with siRNA and protein expression with a HDAC6 targeting protein degrader decreased HGSOC cell proliferation, migration, and viability. Conversely, the selective inhibition of HDAC6 with the catalytic domain inhibitor, Ricolinostat (ACY-1215), inhibited HDAC6 deacetylation of α-tubulin, resulting in a sustained accumulation of acetylated α-tubulin up to 24 h in HGSOC cells, did not produce a robust inhibition of HDAC6 protein function. Inhibition of HGSOC cell proliferation by ACY-1215 was only achieved with significantly higher and non-selective doses of ACY-1215. In summary, we demonstrated, for the first time, that HDAC6 over-expression in HGSOC and all ovarian cancers is a favorable prognostic marker. We provide evidence to suggest that inhibition of HDAC6 catalytic activity with first generation HDAC6 inhibitors has limited efficacy as a monotherapy in HGSOC.