Integrated ATAC-Seq and RNA-Seq Analyses Identify the Motif CGTTTCCGGT as an Arginine Deficiency-Responsive DNA Element in Cancer Cells.

Background/Objectives: Cancer is predicted to become the leading cause of premature mortality worldwide within this century. Among the hallmarks of cancer, metabolic reprogramming has received growing attention, and arginine deprivation therapy (ADT) represents a potential treatment strategy for tumors exhibiting arginine auxotrophy. Colorectal cancer cells frequently suppress the expression of argininosuccinate synthetase 1 (ASS1), rendering them dependent on extracellular arginine. However, how CRC cells adapt to and resist ADT remains largely unknown. Methods: We combined ATAC-seq and RNA-seq analyses with multiple functional assays-including CCK-8 viability, apoptosis detection, wound-healing, and transwell migration tests-to investigate the molecular basis of ADT response in cancer cells. Results: ADT markedly inhibited cancer cell proliferation (p < 0.001) and motility (p < 0.05) across three cell lines. Integrative multi-omics analyses revealed substantial chromatin remodeling and transcriptional reprogramming under ADT, with differentially expressed genes enriched in autophagy and cell-growth-related pathways. Among these, the motif CGTTTCCGGT was identified as an arginine deficiency-responsive DNA element in cancer cells, and C11orf54 showed pronounced downregulation accompanied by reduced chromatin accessibility at its genomic locus. Conclusions: These findings suggest that ADT restricts cancer cell proliferation and migration through chromatin remodeling mediated by the motif CGTTTCCGGT and the downregulation of C11orf54, identifying C11orf54 as a potential target for enhancing the efficacy of arginine deprivation therapy in cancer cells.