SMARCA4 loss reprograms p300 chromatin occupancy to subvert p53-mediated transcriptional repression in ovarian small cell carcinoma

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer driven by biallelic inactivation of SMARCA4 (BRG1), the ATPase subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. Despite its aggressiveness, SCCOHT exhibits a low mutation burden and retains wild-type p53 tumor suppressor. Using an integrative omics approach, we show that SMARCA4 loss redistributes the p300 acetyltransferase to promoters of cell cycle progression genes, increasing histone H3 lysine 27 acetylation (H3K27ac) and promoting transcription that sustains tumor growth. This opposes p53-mediated transcriptional repression at these loci, where co-occupancy of p53 and histone deacetylase HDAC2 are associated with decreased H3K27ac and suppressed gene expression. SMARCA4 restoration or pharmacologic inhibition of p300 suppresses SCCOHT growth, an effect reversed by p53 deletion and accompanied by reactivation of these cell cycle progression genes. Our findings uncover a chromatin-based mechanism whereby SMARCA4 loss subverts p53-mediated transcriptional repression through reprogramming p300 genomic occupancy to sustain oncogenic growth, highlighting p300 as a potential therapeutic target in SCCOHT. Small cell carcinoma of the ovary, hypercalcemic type, is a rare, aggressive cancer caused by SMARCA4 inactivation and features wild-type p53. Here, the authors suggest that loss of SMARCA4 alters chromatin and reprograms p300 binding, undermining p53’s transcriptional repression and promoting cancer growth.