H2BE113K mutation promotes breast cancer metastasis through modulating chromatin dynamics

Cancer progression is driven by the accumulation of DNA mutations and aberrant gene regulation. Recent studies have demonstrated that multiple H3 mutations serve as drivers of tumorigenesis. However, the role and significance of various cancer-associated histone H2B mutations in cancer development remain unknown. Here, we investigate H2BE113K, a missense mutation of histone H2B predominantly found in patients with breast cancer. We show that H2BE113K promotes colony formation in breast cancer. Notably, transcriptomic analysis reveals differential expression of genes in various cancer pathways in H2BE113K cells. The loci with elevated gene expression display increased chromatin accessibility, accompanied by H2BE113K enrichment. Depletion of G3BP2, one of the H2BE113K target genes that has been implicated in breast cancer, reduces the colony formation phenotype in H2BE113K cells. In addition, H2BE113K knock-in mice crossbred with an MMTV-PyMT breast cancer model show elevated lung metastasis. Together, our findings provide critical insights in the mechanistic role of H2BE113K in gene regulation, chromatin function, and breast cancer progression.