KLF6-mediated recruitment of the p300 complex enhances H3K23su and cooperatively upregulates SEMA3C with FOSL2 to drive 5-FU resistance in colon cancer cells

Histone lysine succinylation, an emerging epigenetic marker, has been implicated in diverse cellular functions, yet its role in cancer drug resistance is not well understood. Here we investigated the genome-wide alterations in histone 3 lysine 23 succinylation (H3K23su) and its impact on gene expression in 5-fluorouracil (5-FU)-resistant HCT15 colon cancer cells. We utilized CUT&Tag assays to identify differentially enriched regions (DERs) of H3K23su in 5-FU-resistant HCT15 cells via integration with ATAC-seq and RNA sequencing data. The regulatory network involving transcription factors (TFs), notably FOSL2 and KLF6, and their downstream target genes was dissected using motif enrichment analysis and chromatin immunoprecipitation assays. Our results revealed a strong positive correlation between H3K23su DERs, differentially expressed genes (DEGs) and H3K27ac, indicating that H3K23su enrichment is closely related to gene activation. The DEGs associated with the H3K23su GAIN regions were significantly enriched in pathways related to colorectal cancer, including the Wnt, MAPK and p53 signaling pathways. FOSL2 and KLF6 emerged as pivotal TFs potentially modulating DEGs associated with H3K23su DERs and were found to be essential for sustaining 5-FU resistance. Notably, we discovered that FOSL2 and KLF6 recruit the PCAF–p300/CBP complex to synergistically regulate SEMA3C expression, which subsequently modulates the canonical Wnt–β-catenin signaling pathway, leading to the upregulation of MYC and FOSL2. This study demonstrated that H3K23su is a critical epigenetic determinant of 5-FU resistance in colon cancer cells, exerting its effects through the modulation of critical genes and TFs. These findings indicate that interventions aimed at targeting TFs or enzymes involved in H3K23su modification could represent potential therapeutic strategies for treating colorectal cancers that are resistant to 5-FU treatment. Colon cancer is a major health concern worldwide, with treatments such as chemotherapy often facing challenges due to drug resistance. This study explores why colon cancer cells become resistant to the common chemotherapy drug 5-fluorouracil. The researchers focused on a process called lysine succinylation and its role in drug resistance. Using advanced techniques such as CUT&Tag (a method to study protein–DNA interactions), they examined changes in specific proteins in colon cancer cells resistant to 5-fluorouracil. They found that certain proteins, including FOSL2 and KLF6, help to maintain this resistance by affecting gene expression through pathways such as Wnt–β-catenin. The study concludes that targeting these proteins and pathways could help to overcome drug resistance in colon cancer. Future research may focus on developing new treatments that disrupt these processes, potentially improving outcomes for patients with resistant colon cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.