The ELF1 / IGF2BP2 / FAM111B Cascade Drives Colorectal Cancer Progression and Ferroptosis Resistance

ABSTRACT Epigenetic dysregulation plays a critical role in colorectal cancer (CRC) progression. Our study investigated the role of FAM111B in tumorigenic phenotypes and ferroptosis in CRC and the mechanisms by which epigenetic alterations influence FAM111B expression. Bioinformatics analyses revealed FAM111B expression and predicted the association between IGF2BP2 and FAM111B or ELF1. The influence on cell phenotypes was determined by assessing cell proliferation, migration, apoptosis and ferroptosis. Mechanism analyses were performed using luciferase reporter and ChIP assays. Subcutaneous xenografts were used to evaluate the role in vivo. FAM111B, IGF2BP2 and ELF1 were upregulated in CRC tumours and cell lines. FAM111B downregulation inhibited cell proliferation and migration while inducing apoptosis and ferroptosis. IGF2BP2 increased FAM111B expression by stabilising its mRNA, and ELF1 transcriptionally upregulated IGF2BP2. Moreover, ELF1 modulated FAM111B expression through IGF2BP2. ELF1 knockdown suppressed cell proliferation and migration while triggering apoptosis and ferroptosis, which could be abolished by reintroduction of IGF2BP2 or FAM111B. Additionally, ELF1 depletion diminished the in vivo tumorigenicity of HCT116 cells. The ELF1/IGF2BP2/FAM111B cascade drives CRC progression and ferroptosis resistance. Targeting this cascade may provide a therapeutic avenue for CRC treatment.