YTHDC1 negatively regulates UBE3A to influence RAD51 ubiquitination and inhibit apoptosis in colorectal cancer cells.

YTHDC1, a key protein in the m(6)A-related regulatory network within cells, is involved in multiple cellular processes such as chromatin-related regulation, RNA splicing, and nuclear export. Understanding its role in colorectal cancer (CRC) development and DNA damage repair is critical for the advancement of treatment strategies. Our study found that YTHDC1 was highly expressed in high-malignancy CRC tissues compared with low-malignancy ones. Upon silencing YTHDC1, we observed a pronounced suppression of the proliferation of CRC cell lines, accompanied by a substantial increase in cell apoptosis. Furthermore, we identified RAD51 as a crucial downstream target of YTHDC1. Knocking down YTHDC1 led to a notable decrease in RAD51 protein levels, and silencing RAD51 also inhibited cancer cell proliferation. Interestingly, RNA-sequencing data indicated that the YTHDC1 deletion did not affect RAD51 transcription. However, Western blot revealed that this deletion increased the ubiquitination of RAD51, likely due to the upregulated E3 ligase UBE3A. Ubiquitination experiments subsequently confirmed that RAD51 is indeed one of the substrates of UBE3A. In summary, our study provides novel insights into how YTHDC1 modulates the expression of RAD51 through post-translational modifications. These findings offer valuable information that may potentially contribute to the development of more effective therapeutic strategies for CRC.