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. Here, KLF6 is linked to colonic neoplasm.