Background: 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 treatment, resulting in poor prognosis and short survival. Dynamic reprogramming of chromatin accessibility is crucial for proper regulation of gene transcription associated with cancer drug resistance by providing the gene regulatory machinery with rapid access to the open genomic DNA. Methods: Here, we explored the global chromatin accessibility and transcription changes by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with transcriptome sequencing of both parental and 5-FU-resistant HCT15 cells, followed by integrative analysis to better understand the regulatory network underlying 5-FU resistance in colon cancer cells. Results: A total of 3,175 differentially expressed mRNAs (DEGs), lncRNAs (DELs), and miRNAs (DEMs) related to 5-FU resistance were identified, including significantly upregulated IL33, H19, and miR-17-5p; the downregulated AKR1B10, LINC01012, and miR-125b-5p; and chromatin modifiers such as INO80C, HDAC6, and KDM5A. The construction of the ceRNA regulatory network revealed that H19, HOXA11-AS, and NEAT1 might function as ceRNAs associated with 5-FU resistance in HCT15 cells. Moreover, 9,868 differentially accessible regions (DARs) were obtained, which were positively (r = 0.58) correlated with their nearest DEGs and DELs. The upregulated genes related to 4,937 hyper-accessible regions were significantly enriched in signaling pathways of MAPK, FOX, and WNT, while the 4,931 hypo-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 the AP-1 family, the TF motifs of FOX and KLF family members were highly enriched in hyper- and hypo-accessible regions, respectively. Finally, we obtained several critical TFs and their potential targets associated with DARs and 5-FU resistance, including FOXA1 and KLF3. Conclusion: 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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