Abstract 4319: Epigenetic reprogramming associated with BRCA1 loss of function in ovarian cancer induces enhanced interferon gamma signaling

Abstract

Abstract Inactivating mutations of the breast cancer type 1 susceptibility protein (BRCA1) have been implicated in breast and ovarian cancer (OC) initiation. Having observed differential response of OC cells to histone deacetylase inhibitors (HDACi) dependent on the presence of a functional BRCA1, we mapped promoters marked by acetylation of lysine 9 or lysine 27 of histone H3 (H3K9ac, H3K27ac) by ChIP-sequencing, and measured gene expression by RNA-sequencing in the isogenic OC cell lines UWB1.289 carrying an inactivating mutation of BRCA1 (BRCA1-null) and UWB1.289 cells with restored BRCA1 gene (BRCA1+). Significant differences in promoter levels of H3K9 and H3K27 acetylation were associated with marked alteration of gene expression levels between BRCA-null and BRCA1+ cells and in response to the HDACi, entinostat. Pathway analyses revealed cellular movement, cellular development, cellular growth and proliferation, TGFβ1, TNF, and INF-γ among the top cellular/molecular functions and upstream regulators enriched by the absence of BRCA1 among H3K9ac differentially marked and differentially expressed genes. Importantly, the same pathways and regulators were enriched in response to entinostat in BRCA1+ cells, indicating that changes in gene expression affecting these functions and regulators in BRCA1-null cells depend on promoter-associated histone acetylation. Integrated analyses revealed that TGFβ1 and IFN-γ were also activated in BRCA1-null/or low vs. BRCA1-normal ovarian tumors in the TCGA database. IFN-γ target genes were upregulated at baseline and responded less to IFN-γ stimulation in BRCA1-null vs. BRCA1+ cells. Binding of HDAC1 to promoters of IFN-γ target genes was increased in BRCA1-null cells. Similarly, the BRCA1-null breast cancer cell line HCC1937 responded less to IFN-γ stimulation compared with HCC1937 cells in which BRCA1 was restored. The knockdown of STAT1, the main IFN-γ signaling transduction molecule, inhibited BRCA1+ cell proliferation, but did not affect BRCA1-null cells. We conclude that the transcriptome of BRCA1-null cells and tumors is altered through changes in histone acetylation affecting cancer-related pathways, including IFN-γ cellular responses. These changes could alter tumor progression in BRCA-null OC and impact response to immunotherapy. Citation Format: Horacio Cardenas, Jessica Thomes Pepin, Guanglong Jiang, Salvatore Condello, Kenneth P. Nephew, Yunlong Liu, Daniela Matei. Epigenetic reprogramming associated with BRCA1 loss of function in ovarian cancer induces enhanced interferon gamma signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4319.