The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer Journal Article


Authors: Akano, I.; Hebert, J. M.; Tiedemann, R. L.; Gao, Q.; Xiao, Y.; Prescott, N. A.; Liu, Y.; Tan, K. S.; Bastle, R. M.; Ramakrishnan, A.; Maze, I.; Sidoli, S.; Koche, R. P.; Ganesh, K.; Rothbart, S. B.; David, Y.
Article Title: The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer
Abstract: Histone ubiquitination is a crucial post-translational modification (PTM) regulating chromatin function, yet many histone ubiquitination sites and the enzymes that control them remain poorly understood. Here, we identify SMARCA3, a SWI/SNF-related protein frequently downregulated in colorectal cancer (CRC), as an E3 ubiquitin ligase that targets histone H3 at lysine 23 (H3K23). We demonstrate that SMARCA3 histone ubiquitination activity is stimulated by the repressive H3K9me3 mark. Loss of SMARCA3 reduces both H3K23Ub and H3K9me3, increasing chromatin accessibility at promoters and enhancers enriched for pioneer transcription factor motifs. This chromatin “rewiring” alters the transcriptional landscape, driving upregulation of cancer-promoting genes. We validate this mechanism in CRC cell lines and patient-derived organoids, where SMARCA3 loss reduces H3K23Ub and H3K9me3. In xenograft mouse models, overexpression of wild-type SMARCA3, but not a RING domain mutant, suppresses tumor growth. Together, our findings define SMARCA3 as a key chromatin regulator contributing to CRC pathogenesis through epigenetic mechanisms. © 2025 Elsevier Inc.
Keywords: epigenetics, histone, ubiquitination, methylation, chromatin, accessibility, cancer, ring, e3 ligase
Journal Title: Molecular Cell
Volume: 85
Issue: 15
ISSN: 1097-2765
Publisher: Cell Press  
Publication status: Published
Date Published: 2025-08-07
Online Publication Date: 2025-07-17
Start Page: 2885
End Page: 2899.e8
Language: English
DOI: 10.1016/j.molcel.2025.06.020
PROVIDER: scopus
PMCID: PMC12327810
PUBMED: 40680746
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Yael David -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Richard Patrick Koche
    180 Koche
  2. Karuna   Ganesh
    70 Ganesh
  3. Kay See   Tan
    245 Tan
  4. Jakob M Hebert
    6 Hebert
  5. Yang Xiao
    3 Xiao
  6. Qingzeng Gao
    4 Gao
  7. Ifeh Ariela Akano
    2 Akano