2. Academic Validation
  3. SMARCA4 loss reprograms p300 chromatin occupancy to subvert p53-mediated transcriptional repression in ovarian small cell carcinoma

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

  • Nat Commun. 2026 Jun 15. doi: 10.1038/s41467-026-74204-8.
Giulio Aceto 1 2,  Kexin Liu 1 2,  Azadeh Arabzadeh 1 2,  Shuhe Tsai 3,  Yibo Xue 1 2,  Anie Monast 1 2,  Virginie Pilon 1 2,  Mengke Han 3 4,  Geneviève Morin 1 2,  Kitty Pavlakis 5,  Lili Fu 6,  Morag Park 1 2,  William D Foulkes 7 8 9,  Yemin Wang 10 11 12,  Sidong Huang 13 14 15
Affiliations

Affiliations

  • 1 Department of Biochemistry, McGill University, Montreal, Canada.
  • 2 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada.
  • 3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
  • 4 Department of Basic and Translational Research, British Columbia Cancer Research Institute, Vancouver, Canada.
  • 5 Department of Pathology, IASO women's hospital, Athens, Greece.
  • 6 Department of Pathology, McGill University Health Centre, Montreal, Canada.
  • 7 Department of Human Genetics, McGill University, Montreal, Canada.
  • 8 SCCOHT/SMARCA4 Registry, Research, Institute of the McGill University Health Centre, Montreal, Canada.
  • 9 Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Canada.
  • 10 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. [email protected].
  • 11 Department of Basic and Translational Research, British Columbia Cancer Research Institute, Vancouver, Canada. [email protected].
  • 12 Ovcare Cancer Research Centre and Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada. [email protected].
  • 13 Department of Biochemistry, McGill University, Montreal, Canada. [email protected].
  • 14 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada. [email protected].
  • 15 Department of Human Genetics, McGill University, Montreal, Canada. [email protected].
PMID: 42297809 DOI: 10.1038/s41467-026-74204-8
Abstract

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.

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