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Abstract
Introduction/Background Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in irradiation and drug resistance. We aimed to explore the biological function and clinical significance of the 5-methylcytosine (m5C) methyltransferase NSUN6 in cervical cancer radiosensitivity.
Methodology Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in irradiation and drug resistance. We aimed to explore the biological function and clinical significance of the 5-methylcytosine (m5C) methyltransferase NSUN6 in cervical cancer radiosensitivity.
Results We found a higher abundance of m5C modification in resistant CC samples, and NSUN6 is the essential m5C-regulated gene in CC radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Moreover, higher NSUN6 expression was associated with radioresistance in patient-derived 3D bioprinted CC organoids. Mechanistically, NDRG1 is one of the downstream target genes of NSUN6 identified by integrated m5C-seq, RNA-seq, and functional validation. NSUN6 promotes the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF binds explicitly to the m5C-labeled NDRG1 mRNA and enhances NDRG1 mRNA stability. NDRG1 overexpression promotes the DNA damage repair process, which in turn leads to radioresistance in cervical cancer.
Conclusion RNA m5C hypermethylation and NSUN6 overexpression are associated with radioresistance in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6-ALYREF-m5C/NDRG1 axis. NSUN6 expression is a potential biomarker of radiosensitivity and a therapeutic target for cervical cancer.
Disclosures The authors declare no competing interests.
