Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy in women. The low survival rate is largely due to drug resistance. Approximately 80% of patients who initially respond to treatment relapse and become drug-resistant. The lack of effective second-line therapeutics remains a substantial challenge for BRCA-1/2 wild-type HGSOC patients. Histone Deacetylases (HDACs) are promising targets in HGSOC treatment; however, the mechanism and efficacy of HDAC inhibitors are understudied in HGSOC. In order to consider HDACs as a treatment target, an improved understanding of their function within HGSOC is required. This includes elucidating HDAC6-specific protein–protein interactions. In this study, we carried out substrate trapping followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate HDAC6 catalytic domain (CD)-specific interactors in the context of BRCA-1/2 wild-type HGSOC. Overall, this study identified new HDAC6 substrates that may be unique to HGSOC. The HDAC6-CD1 mutant condition contained the largest number of significant proteins compared to the CD2 mutant and the CD1/2 mutant conditions, suggesting the HDAC6-CD1 domain has catalytic activity that is independent of CD2. Among the identified substrates were proteins involved in DNA damage repair including PARP proteins. These findings further justify the use of HDAC inhibitors as a combination treatment with platinum chemotherapy agents and PARP inhibitors in HGSOC.

2-(Difluoromethyl)-1,3,4-oxadiazoles: The Future of Selective Histone Deacetylase 6 Modulation?

“…HDAC6 stands out among HDAC isoforms due to its distinct structural features, localization, and substrate range . Notably, HDAC6 features two independently active catalytic domains (CD1 and CD2) and a zinc finger serving as an ubiquitin-binding domain. , Initially identified as a tubulin deacetylase, HDAC6 also catalyzes the deacetylation of various other proteins . Moreover, it plays a pivotal role in modulating cortactin, the Alzheimer-related tau protein, and the chaperone HSP90. , Consequently, HDAC6 is crucial for various cellular processes (see Figure for representative examples), including cell motility, proliferation, apoptosis, and the aggresomal pathway, thereby making it a valuable target for drug development …”

“…5 Notably, HDAC6 features two independently active catalytic domains (CD1 and CD2) and a zinc finger serving as an ubiquitin-binding domain. 1,7 Initially identified as a tubulin deacetylase, HDAC6 also catalyzes the deacetylation of various other proteins. 8 Moreover, it plays a pivotal role in modulating cortactin, 9 the Alzheimer-related tau protein, 10 and the chaperone HSP90.…”