P53 Inhibition Diminishes IGSF9 Gene Activity to Promote DNA Repair and Exacerbate the Progression of Colon Cancer

Colon cancer (CC) is a malignancy with high global incidence and mortality, and elucidating its underlying molecular mechanisms is critical for improving prognostic assessment and therapeutic strategies. In this study, transcriptomic data from a large cohort of CC samples and a limited number of normal controls from the TCGA database were used to construct a multigene prognostic risk model using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. The expression of key prognostic genes, including immunoglobulin superfamily member 9 (IGSF9), was further validated in CC tissues by PCR and Western blotting. Functional assays were performed in HCT116 cells to investigate the biological effects of IGSF9 overexpression and its regulatory relationship with p53. The prognostic model identified IGSF9 as a gene significantly associated with patient survival. Although IGSF9 expression was reduced at both the mRNA and protein levels in CC tissues, its overexpression in vitro markedly promoted apoptosis, alleviated DNA damage, and suppressed cell migration and invasion. Notably, silencing of p53 partially reversed the tumor-suppressive effects induced by IGSF9 overexpression, indicating that IGSF9 exerts its biological functions in a p53-dependent manner. Collectively, these findings demonstrate that IGSF9 acts as a tumor suppressor in colorectal cancer and regulates DNA damage responses and apoptosis through a mechanism partially dependent on p53, highlighting its potential value as a prognostic biomarker and therapeutic target in CC.