RT Journal Article
SR Electronic
T1 Targeting BRPF3 moderately reverses olaparib resistance in high grade serous ovarian carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.21.473688
DO 10.1101/2021.12.21.473688
A1 Benjamin G. Bitler
A1 Tomomi M. Yamamoto
A1 Alexandra McMellen
A1 Hyunmin Kim
A1 Zachary L. Watson
YR 2022
UL http://biorxiv.org/content/early/2022/11/07/2021.12.21.473688.abstract
AB Background PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) and epigenetic readers have known functions in DNA repair and replication. Our objectives are to examine their expression and activities in the context of PARPi-resistant HGSOC, and to determine if targeting H3K14ac or associated proteins has therapeutic potential.Results Using mass spectrometry profiling of histone modifications, we observed increased H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance.Conclusions This study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins, such as PCAF, or accessory proteins, such as BRPF3, may play a more direct role compared to direct histone acetyltransferase functions in PARPi response.Competing Interest StatementThe authors have declared no competing interest.