NSUN2 Knockdown Promotes the Ferroptosis of Colorectal Cancer Cells Via m5C Modification of SLC7A11 mRNA.

Abstract

The high occurrence and death rates of colorectal cancer (CRC) make it a major health concern. Recent studies have identified NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase, as a key regulator in various tumor types. However, how exactly NSUN2-mediated m5C alteration affects CRC is still a mystery. This study seeks to understand how NSUN2 contributes to the growth and death of colorectal cancer cells. New tissue samples were taken in order to investigate NSUN2 expression in CRC. In vitro tests were performed to evaluate NSUN2's function. We used m5C-methylated-RNA immunoprecipitation and RNA stability experiments to find out how NSUN2 works on Solute carrier family 7 member 11 (SLC7A11, also called xCT). Downregulation of NSUN2 limits CRC cell growth and induces ferroptosis, as we show that NSUN2 was substantially expressed in CRC. In terms of the molecular mechanism, NSUN2 controls the translation and stability of SLC7A11 mRNA by regulating its m5C methylation. Functional tests show that SLC7A11 compensates for the NSUN2 knockdown-induced decrease in cell proliferation. Additionally, SLC7A11 overexpression restores ferroptosis to CRC cells after NSUN2 knockdown. These findings emphasize NSUN2's crucial role in modulating colorectal cancer cell growth and survival via SLC7A11, pointing to promising new therapeutic targets.