NSUN2-mediated RNA m⁵C modification drives multiple myeloma progression by enhancing the stability of HIP1 mRNA

RNA 5-methylcytosine (m⁵C) modification is a crucial epigenetic regulation, and aberrant m⁵C methylation is associated with the pathogenesis of certain cancers. However, the role and regulatory mechanisms of RNA m⁵C modification in multiple myeloma (MM) remain unclear. This study aimed to investigate the function and regulatory mechanisms of the primary m⁵C methyltransferase, NOP2/Sun RNA methyltransferase family member 2 (NSUN2), in MM. The results demonstrated NSUN2 overexpression in patients with MM, and higher NSUN2 levels were associated with poorer outcomes. In addition, elevated global RNA m⁵C levels were identified in specimens from MM patients, and NSUN2 knockdown decreased RNA m⁵C levels. Furthermore, NSUN2 knockdown suppressed cell proliferation, promoted apoptosis in vitro, and restrained the progression of xenograft tumors in vivo. Mechanistically, m⁵C methylated RNA immunoprecipitation (meRIP)-sequencing and RIP-quantitative polymerase chain reaction (RIP-qPCR) assays were applied to screen the candidate targets of NSUN2-mediated m⁵C modification and huntingtin interacting protein 1 (HIP1) was identified as the target. NSUN2-mediated m⁵C methylation upregulated HIP1 by enhancing HIP1 mRNA stability. Moreover, HIP1 overexpression counterbalanced the inhibitory effect of NSUN2 knockdown. In conclusion, we propose a novel mechanistic insight into the NSUN2/m⁵C-HIP1 signaling axis that contributes to the pathogenesis of MM. Thus, NSUN2 can be a novel prognostic biomarker in patients with MM and targeting NSUN2 may be a promising therapeutic strategy.