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SMARCA4 loss reprograms p300 chromatin occupancy to subvert p53-mediated transcriptional repression in ovarian small
Giulio Aceto1,2, Kexin Liu1,2, Azadeh Arabzadeh1,2
1Department of Biochemistry, McGill University, Montreal, Canada.
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.
Insights
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is driven by SMARCA4 loss. This rewires gene expression, promoting cancer growth, but p300 inhibition offers a potential therapeutic strategy.
Area of Science:
- Oncology
- Epigenetics
- Cancer Genomics
Background:
- Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive malignancy.
- SCCOHT is characterized by biallelic inactivation of SMARCA4 (BRG1), a key component of the SWI/SNF chromatin remodeling complex.
- Despite its aggressive nature, SCCOHT has a low mutation burden and retains wild-type p53.
Purpose of the Study:
- To elucidate the molecular mechanisms driving SCCOHT pathogenesis following SMARCA4 loss.
- To investigate the interplay between SMARCA4, p53, and chromatin remodeling in SCCOHT.
- To identify potential therapeutic targets for SCCOHT.
Main Methods:
- Integrative omics analysis (genomics, epigenomics, transcriptomics).
- Chromatin immunoprecipitation assays to assess protein occupancy.
- Functional studies involving SMARCA4 restoration and p300 inhibition.
- Assessment of tumor growth in response to genetic and pharmacologic interventions.
Main Results:
- SMARCA4 loss leads to the redistribution of the p300 acetyltransferase to cell cycle progression gene promoters.
- This redistribution increases histone H3 lysine 27 acetylation (H3K27ac) and promotes oncogenic transcription, counteracting p53-mediated repression.
- SMARCA4 restoration or p300 inhibition suppressed SCCOHT growth, with effects reversed by p53 deletion.
Conclusions:
- SMARCA4 loss drives SCCOHT by reprogramming p300 binding to promote cell cycle gene transcription, overriding p53-mediated suppression.
- This chromatin-based mechanism highlights a critical vulnerability in SCCOHT.
- p300 represents a promising therapeutic target for treating SCCOHT.
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