YTHDF3 mediates HNF1α regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner

Radiotherapy, as an important primary treatment, has effectively improved the survival of patients with cervical cancer (CC). Some patients, however, do not benefit optimally from radiotherapy because of radio-resistance. Therefore, identifying radio-resistance biomarkers and unravelling the underlying mechanisms is of critical importance for these patients. In the present study, we found significant upregulation of hepatocyte nuclear factor 1-alpha (HNF1 alpha) expression in radio-resistant cervical cancer tissues and cell lines. Depletion of HNF1 alpha reduced and overexpression of HNF1 alpha promoted the resistance of CC cells to irradiation in vitro and in vivo. HNF1 alpha positively regulated DNA repair protein RAD51 homologue 4 (RAD51D) at the protein level but not at the mRNA level. Mechanistically, upregulation of HNF1 alpha enhanced YTH domain-containing family protein 3 (YTHDF3) transcription, which in turn promoted RAD51D mRNA N-6-methyladenosine (m6A) modification. YTHDF3 mediates HNF1 alpha regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner. The HFN1 alpha/YTHDF3/RAD51D regulatory axis was found to play a critical role in conferring radio-resistance of CC cells. In conclusion, dysregulation of the HFN1 alpha/YTHDF3/RAD51D axis may promote the radio-resistance of CC cells. Blocking this pathway may provide therapeutic benefits against CC radio-resistance.