SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in colorectal cancer

Histone ubiquitination is an important post-translational modification (PTM) that mediates diverse chromatin functions1-3. However, our understanding of the enzymes that regulate histone ubiquitination, along with their relationships to human disease, remains limited. Here, we identify the tumor suppressor SMARCA3 as a histone H3K23 E3 ubiquitin ligase that functions through a distinct mechanism from its characterized role in post-replication repair. We show that cellular depletion of SMARCA3 results in reduced H3K9me3 levels and altered genomic distribution, leading to cancer-associated rewiring of cellular transcriptional programs . Using both cell lines and patient-derived organoids, we demonstrate that colorectal cancer tumors driven by downregulation of SMARCA3 display similar decreases in H3K9me3, as well as alterations in the expression of cancer-promoting genes. Taken together, our data indicate critical roles for SMARCA3 in maintaining chromatin integrity, and provide a mechanism through which its normal tumor-suppression function may precipitate colorectal cancer when perturbed. ChIP-seq analysis of H3K9me3 in both wild type vs. SMARCA3 knockout 293T cells