NSUN2 contributes to the RB malignant progression and Glycolysis by mediating the m5C methylation modification of HKDC1.

Retinoblastoma (RB) is a malignant neoplasm originating from photoreceptor precursor cells that is common in children under 3 years of age. NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a major methyltransferase that catalyzes mammalian mRNA 5-methylcytosine (m5C) modification and has been implicated in a variety of diseases, but its mechanism in RB is still incomplete. NSUN2 was up-regulated in RB and was associated with the poor survival of patients. Silencing NSUN2 blocked the malignant behaviors of RB cells. In Y79 cells, the differentially expressed genes (DEGs) after knocking down NSUN2 were mainly concentrated in the glycolytic pathway from the GSE214685 dataset, and NSUN2 down-regulation restrained the glycolysis of RB cells. What's more, the m5C modification and mRNA stability of hexokinase domain component 1 (HKDC1) were mediated by NSUN2 and Y-box binding protein 1 (YBX1). Mechanically, NSUN2 promoted RB malignant behaviors and glycolysis in vitro via HKDC1 and accelerated tumor growth in vivo. Our study put forward a new mechanism to regulate RB progression, namely, NSUN2 and YBX1 synergistically promote malignant progression and glycolysis of RB by mediating HKDC1 m5C modification.