Differential histone deacetylase inhibitor-induced perturbations of the global proteome landscape in the setting of high-grade serous ovarian cancer

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Abstract

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in women. Its low survival rate is attributed to late detection, relapse, and drug resistance. The lack of effective second-line therapeutics remains a significant challenge. There is an opportunity to incorporate the use of histone deacetylase inhibitors (HDACi) into HGSOC treatment. However, the mechanism and efficacy of HDACi in the context of BRCA-1/2 mutation status is understudied. Therefore, we set out to elucidate how HDACi perturb the proteomic landscape within HGSOC cells. In this work, we used TMT labeling followed by data-dependent acquisition LC-MS/MS to quantitatively determine differences in the global proteomic landscape across HDACi-treated CAOV3, OVCAR3, and COV318 (BRCA-1/2 wildtype) HGSOC cells. We identified significant differences in the HDACi-induced perturbations of global protein regulation across CAOV3, OVCAR3, and COV318 cells. The HDACi Vorinostat and Romidepsin were identified as being the least and most effective in inhibiting HDAC activity across the three cell lines, respectively. Our results provide a justification for the further investigation of the functional mechanisms associated with the differential efficacy of FDA-approved HDACi within the context of HGSOC. This will enhance the efficacy of targeted HGSOC therapeutic treatment modalities that include HDACi.

Original languageEnglish (US)
JournalProteomics
DOIs
StateAccepted/In press - 2022

Bibliographical note

Funding Information:
We thank previous Thomas lab member Shannon Culbert, a summer undergraduate intern, for her contribution to acquiring the ES‐2 cell line data. Mass spectrometry data were acquired in the Analytical Biochemistry Shared Resource of the University of Minnesota Masonic Cancer Center, supported in part by the National Cancer Institute (Cancer Center Support Grant P30 CA077598). S.N.T. acknowledges funding from the National Institutes of Health's National Center for Advancing Translational Sciences, Grant No. UL1TR002494, via the University of Minnesota's Clinical and Translational Science Institute. S.N.T. also acknowledges funding from the V Foundation from Cancer Research and startup funds provided by the University of Minnesota Department of Laboratory Medicine and Pathology. J.M.D. and S.N.T. acknowledge funding from a Mayo Clinic Ovarian SPORE Developmental Research Project (P50 CA136393).

Publisher Copyright:
© 2022 The Authors. Proteomics published by Wiley-VCH GmbH.

Keywords

  • high-grade serous ovarian cancer (HGSOC)
  • histone deacetylase inhibitor (HDACi)
  • mass spectrometry
  • tandem mass tags (TMT)

PubMed: MeSH publication types

  • Journal Article

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