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KLF6-mediated recruitment of the p300 complex enhances H3K23su and cooperatively upregulates SEMA3C with FOSL2 to drive 5-FU resistance in colon cancer cells
KLF6通过募集p300复合体增强组蛋白H3K23琥珀酰化修饰，并与FOSL2协同上调SEMA3C驱动结肠癌细胞对5-FU的耐药性。

Histone lysine succinylation, as an emerging epigenetic mark, has been found to play important roles in various cellular functions, but its mechanisms in cancer drug resistance remain unclear. In this study, by integrating ATAC-seq and RNA-seq data, CUT&Tag technology was employed to reveal genome-wide histone H3 lysine 23 succinylation (H3K23su) modification profiles and its regulatory effects on gene expression in 5-fluorouracil (5-FU)-resistant HCT15 colon cancer cells. Through motif enrichment analysis and chromatin immunoprecipitation assays, we dissected a transcription factor regulatory network centered on FOSL2 and KLF6 and their downstream target genes. The results showed that H3K23su differentially enriched regions (DERs) were significantly positively correlated with differentially expressed genes (DEGs) and H3K27ac modifications, indicating that H3K23su enrichment is closely associated with gene activation. DEGs associated with H3K23su-gained regions were significantly enriched in key colorectal cancer pathways, including Wnt, MAPK, and p53 signaling pathways. Mechanistic studies revealed that FOSL2 and KLF6 synergistically regulate SEMA3C expression by recruiting the PCAF-p300/CBP complex, which in turn activates the canonical Wnt-β-catenin signaling pathway to upregulate MYC and FOSL2, ultimately maintaining 5-FU resistance. This study demonstrates that H3K23su is a critical epigenetic determinant influencing 5-FU resistance in colon cancer cells through the regulation of key genes and transcription factors. Intervention strategies targeting H3K23su-associated transcription factors or enzymes may provide new avenues for the treatment of 5-FU-resistant colorectal cancer.
Original article: https://www.nature.com/articles/s12276-025-01424-1