RNA binding motif protein RBM41 promotes colorectal tumorigenesis by impeding the maturation of NDRG1 pre-mRNA

Abstract Colorectal cancer (CRC) is a prevalent and highly lethal malignancy. RNA-binding motif (RBM) proteins have been demonstrated in CRC pathogenesis. However, the biological function and regulatory mechanisms of RBM41 in CRC remain poorly understood. Here, we demonstrate that RBM41 is significantly elevated in CRC tissues and is associated with poor prognosis in patients. Overexpression of RBM41 can enhance the malignant proliferation phenotype of CRC cells; in contrast, inhibition of RBM41 significantly decreases CRC cell proliferation and induces autophagic cell death and apoptosis in HT29 and SW480 cells. Mechanistically, RBM41 interferes with the processing of N-myc downregulated gene 1 ( NDRG1 ) pre-mRNA by directly binding to its 3’ untranslated region (3’ UTR), thereby decreasing the mature transcript and protein levels of tumor suppressor NDRG1 . Concurrent knockdown of NDRG1 reversed the oncogenic functions of RBM41 in HT29 cells and in fast-growing xenograft tumors in vivo. Moreover, patient-derived organoid (PDO) models with high RBM41 expression exhibited increased resistance to 5-fluorouracil, oxaliplatin, and irinotecan. In summary, our findings demonstrate that RBM41 promotes CRC progression by post-transcriptionally repressing NDRG1 , underscoring its potential as a promising therapeutic target for CRC.