Genome-wide alteration of histone3 lysine23 succinylation contribute to 5-fluorouracil resistance in colon cancer cells
Although widely used in chemotherapy for colon cancer, 5-fluorouracil (5-FU) resistance is the main reason greatly limiting the efficacy of current therapies, leading to poor patient prognosis and survival. Histone lysine succinylation plays a vital role in various diseases by influencing gene expression and chromatin structure. However, limited information is currently available about the role of H3K23 succinylation associated with 5-FU resistance in colon cancer cells (CCCs). Here we explored the systematic alterations of H3K23s succinylation using the Cleavage Under Targets and Tagmentation (CUT&Tag), followed by integrated analysis of multi-omics data to identify potential regulators and their targets associated with differentially enriched regions (DERs) in the parental and 5-FU-resistant HCT15 colon cancer cells. More than 60,000 high-quality peaks were obtained from each sample with higher signal enriched at gene promoter regions. A total of 13,622 H3K23su DERs were identified in 5-FU-resistant HCT15 cells compared to control, which was positively (r = 0.68) correlated with their nearest differentially expressed genes (DEGs). The up-regulated DEGs associated with H3K23su GAIN regions are mainly involved in colorectal cancer, MAPK, Ras, and p53 signaling pathways, while the down-regulated DEGs related to H3K23su LOSS regions significantly enriched in the signaling pathways of Wnt and HIF-1. DNA motif analyses of the DER sequences showed that, besides AP-1, the members of FOX, GATA, and TEAD transcription factor (TF) families were potentially enriched in GAIN or LOSS regions with different preferences. Moreover, differentially expressed TFs and their potential targets associated with H3K23su DERs were identified, including FOSL21, FOXA1 and HNF1B, and known and predicted interactions among these critical TFs were further illustrated. These data provided clear insights and resources for an improved understanding of the role of H3K23su related to 5-FU resistance in colon cancer cells based on the multi-omics data, which allowed for the detection of epigenomic profiles, potential regulatory TFs, cis-regulatory elements, and therapeutic targets. Overall design: Cleavage under targets and tagmentation (CUT&Tag) was used for detection of H3K23 succinylation and H3K27 acetylation in parental and 5-fluorouracil-resistant HCT15 colon cancer cells, and then integrated analysis of multi-omics data, including mRNA-seq and ATAC-seq, was performed to investigate the role of H3K23su in CCCs associate with 5-FU resistance.