NAT10-mediated acC modification promotes stemness and chemoresistance of colon cancer by stabilizing NANOGP8.

Background: Colon cancer (CC) stem cells can self-renew as well as expand, thereby promoting tumor progression and conferring resistance to chemotherapeutic agents. The acetyltransferase NAT10 mediates N4-acetylcytidine (acC) modification, which in turn drives tumorigenesis, metastasis, stemness properties maintenance, and cell fate decisions. Nonetheless, the specific involvement of acC modification mediated by NAT10 in regulating stemness and chemosensitivity in CC remains undetermined.

Methods: The levels of NAT10 in normal colon and chemoresistant CC tissues were determined utilizing quantitative real-time polymerase chain reaction alongside immunohistochemistry. Assessing cancer cell stemness and chemosensitivity was conducted by various methods including spheroid and colony formation, western blotting, and flow cytometry. RNA-Seq was used to identify target genes, and RNA immunoprecipitation analysis was used to explore the potential mechanisms.

Results: We observed NAT10 overexpression and increased acC modification levels in chemoresistant CC tissues. The and analysis findings suggested that NAT10 promoted CC cell stemness while suppressing their chemosensitivity. Conversely, Remodelin, a NAT10-specific inhibitor, enhanced CC cell chemosensitivity. Mechanistically, NAT10 increased the level of acC modification and promoted mRNA stability.

Conclusions: NAT10 promotes the maintenance of stemness and chemoresistance in CC cells by augmenting the mRNA stability of . The inhibition of NAT10 via Remodelin improves chemotherapeutic efficacy and impedes CC progression.