PT  - JOURNAL ARTICLE
AU  - Benjamin G. Bitler
AU  - Tomomi M. Yamamoto
AU  - Alexandra McMellen
AU  - Hyunmin Kim
AU  - Zachary L. Watson
TI  - BRPF3 knockdown or inhibition moderately reverses olaparib resistance in high grade serous ovarian carcinoma, but depletion of H3K14 acetylation has no effect
AID  - 10.1101/2021.12.21.473688
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.21.473688
4099  - http://biorxiv.org/content/early/2021/12/22/2021.12.21.473688.short
4100  - http://biorxiv.org/content/early/2021/12/22/2021.12.21.473688.full
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) have known functions in DNA repair and replication, but their expression and activities have not been examined in the context of PARPi-resistant HGSOC.Results Using mass spectrometry profiling of histone modifications, we observed altered 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 greater role in PARPi response than acetyltransferase functions.Competing Interest StatementThe authors have declared no competing interest.