Molecular Mechanism of NSUN6‐Mediated Epigenetic Modifications in the Malignant Progression of Colorectal Cancer Cells

Colorectal cancer (CRC) stands as a widespread gastrointestinal malignancy, marked by high morbidity and mortality, and poses a substantial threat to global public health. This research aims to explain the significance of NSUN6 in CRC progression. Tumor tissues were harvested from CRC patients, with subsequent analysis of the association between NSUN6 expression and clinical features. After intervening in NSUN6 expression in CRC cells and normal cells, cell proliferation, apoptosis, migration, and invasion were detected. m5C modification and ALYREF enrichment on KLF1 were analyzed. The binding of KLF1 to USP15 was detected. We found that NSUN6 expression was increased and correlated with the clinical characteristics of CRC patients. After downregulation of NSUN6, cell proliferation was decreased, apoptosis was increased, and cell migration and invasion were reduced. NSUN6 stabilizes KLF1 mRNA via ALYREF-dependent m5C modification, thereby enhancing KLF1 expression. KLF1 promotes USP15 expression. Overexpression of KLF1 or USP15 alleviated the suppressing effect of NSUN6 downregulation on the malignant progression of CRC cells. NSUN6 downregulation inhibited tumor growth and liver/lung metastasis, which were promoted upon KLF1 overexpression. In conclusion, NSUN6 mediates m5C modification and promotes the malignant progression of CRC cells via the KLF1/USP15 axis.