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.