Abstract

This study investigates the novel epigenetic mechanism underlying resistance to arginine deprivation therapy (ADT) in tumors, with implications for therapeutic targeting. In brief: 1. ADT potently suppresses CRC proliferation and migration while exerting only a limited pro-apoptotic effect. 2. Integrative ATAC-seq and RNA-seq analyses identify the motif CGTTTCCGGT as an arginine deficiency-responsive DNA element in cancer cells and reveal that the transcriptional inhibition of C11orf54 with ADT is associated with ETV5 . 3. ATAC-seq demonstrates reduced chromatin accessibility at the C11orf54 locus in ADT-treated cells and functional validation via luciferase reporter assays confirms suppressed C11orf54 promoter activity with ADT. 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. Amon