GSE131140
Interpheron-? signaling is associated with BRCA-1 loss-of-function mutations in high grade serous ovarian cancer [ChIP-seq]
Purpose: Loss-of-function mutations of the breast cancer type 1 susceptibility protein (BRCA1) are associated with breast (BC) and ovarian cancer (OC).  We assessed responses to histone deacetylase inhibitors (HDACi) and performed genome-wide RNA and chromatin immunoprecipitation (ChIP)-sequencing in isogenic OC cells UWB1.289 (carrying a BRCA1 mutation) and UWB1.289 transduced with wild type BRCA1.   Experimental Design: Gene expression profiles of cells harboring mutated vs. functional BRCA1 and treated with the HDACi were integrated with chromatin mapping of histone H3 lysine 9 or 27 acetylation (H3K9ac, H3K27ac) at active promoters and enhancers.  Key pathways found deregulated in BRCA1 mutated cells were validated.   Results: Gene networks activated in BRCA1-mutated vs. BRCA1+ OC cells relate to Cellular Movement, Cellular Development, Cellular Growth and Proliferation and shared upstream regulators included TGFb1, TNF, and IFN-g.  The IFN-g pathway was significantly altered in response to HDACi in BRCA1+ vs. BRCA1-mutated cells and in BRCA1-mutated/or low vs. BRCA1-normal ovarian tumors profiled in the TCGA database. Key IFN-?-induced genes upregulated at baseline in BRCA1-mutated vs. BRCA1+ OC and BC cells included CXCL10, CXCL11, and IFI16. Increased localization of STAT1 to the promoters of these genes was observed in BRCA1-mutated cells, resulting in diminished cellular responses to IFN-? or to STAT1 knockdown. The IFN-g signature was associated with improved survival among tumors profiled by the TCGA.   Conclusions: Transcriptomic changes affecting IFN-? response are associated with inactivating BRCA1 mutations in OC. These alterations could contribute to diminished anti-tumor immunity in BRCA1 mutated cells or tumors. Overall design: H3K9ac and H3K27ac levels were compared between BRCA1-null UWB1.289  ovarian cancer cells and UWB1.289 cells with BRCA1 restored.