HDAC6 Degradation Inhibits the Growth of High-Grade Serous Ovarian Cancer Cells
Authors: Karolina Weiner-Gorzel
Aaron Maguire
Caitlin Beggan
Sharon O&#x27;Toole
Tara Byrne
Fengyu Zhang
Stephen Bridgett
Fiona Furlong
Patricia Fitzpatrick
Ahlam Ali
John O&#x27;Leary
Amanda McCann
Journal: Cancers (2020)
Discipline: CLINICAL MEDICINE
Keywords: ACY-1215; HDAC6; HGSOCs; cisplatin; paclitaxel
Affiliations: Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast BT97BL, UK., School of Pharmacy, Queen's University, Belfast BT97BL, UK., UCD Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin (UCD), Belfield, Dublin 4, Ireland., Department of Histopathology, Trinity College Dublin and Trinity St James's Cancer Institute, St. James's Hospital, Dublin 8, Ireland., Emer Casey Molecular Pathology Research Laboratory, Coombe Women's & Infants University Hospital, Dublin D08, Ireland., Department of Obstetrics & Gynaecology, Trinity College Dublin and Trinity St James's Cancer Institute, Trinity Centre for Health Sciences, St James's Hospital, Dublin 2, Ireland., Department of Pathology, Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital, Dublin 9, Ireland., School of Public Health, Physiotherapy & Sports Science, College of Health and Agricultural Sciences, University College Dublin (UCD), Belfield, Dublin 4, Ireland.

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. 

Retracted: No

PubPeer comments:
 Figure 5D. * Blue boxes: Two panels in the spleen row appear to show an overlap. Reported to the journal together with 28 other papers in the summer of 2015, with a friendly reminder in April 2017, but no answer. With the exception of one paper, the journal did not correct or retract a single paper from this set. Could the authors please clarify if the journal contacted them back in 2015? ![file] ,