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Genome-wide alteration of histone3 lysine23 succinylation contribute to 5-fluorouracil resistance in colon cancer cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234735 | GEO | 2023/06/20

REPOSITORIES: GEO

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Project description:5-Fluorouracil (5-FU) is one of the most effective and widely used chemotherapeutic drugs in the treatment of colon cancer. Yet chemoresistance is a common feature of colon cancer, resulting in poor prognosis and short survival. Dynamic reprogramming of chromatin accessibility allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression via direct transcription factor activation and regulatory element-binding. To better understand the regulatory network underlying 5-FU resistance in colon cancer cells, we explored the systematic alterations of chromatin accessibility and transcript expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with transcriptome sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in 5-FU-resistant HCT15 (HCT15-FR) cells. A total of 3175 differentially expressed mRNAs (DEGs), lncRNAs (DELs) and miRNAs (DEMs) related to 5-FU resistance were identified, including dramatically up-regulated IL33, H19, miR-17-5p, significantly down-regulated AKR1B10, LINC01012, miR-125b-5p, and potential chromatin modifiers such as INO80C, HDAC6 and KDM5A. A competitive endogenous RNAs (ceRNAs) regulatory network was established based on information about interactions among DEGs, DELs and DEMs, suggesting that H19, HOXA11-AS and NEAT1 might function as ceRNAs associate with 5-FU resistance in HCT15 cells. By integrating with transcriptome data, 9868 DARs were identified in HCT15-FR cells compared to control, which were positively (r = 0.58) correlated with their nearest DEGs and DELs. The up-regulated genes related to 4937 increased chromatin-accessible regions were significantly enriched in signaling pathways of MAPK, FOX and WNT, while the 4931 decreased chromatin-accessible regions were considered to be involved in declined biosynthesis of amino acids and nucleotide sugars, signaling pathways of Notch, and HIF-1. Analyses of the DAR sequences revealed that, besides AP-1 family, the TF DNA-binding motifs of FOX and KLF family members were highly enriched in hyper- and hypo-accessible regions, respectively. Moreover, relationships of critical TFs and their potential targets associated with DARs were identified, such as FOXA1, RUNX2, KLF3 and GRHL2. These data provided clear insights and valuable resources for an improved understanding of the non-genetic landscape of 5-FU-resistant colon cancer cells based on chromatin accessibility and transcript levels, which allowed for genome-wide detection of TF-binding sites, potential cis-regulatory elements and therapeutic targets.

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Genome-wide alteration of histone3 lysine23 succinylation contribute to 5-fluorouracil resistance in colon cancer cells

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