VIRMA Accelerates the Tumorigenesis of Prostate Cancer via Regulating the m6A Modification of NSMCE2 to Eliminate the Generation of Reactive Oxygen Species.

Abstract

Objectives: N6-methyladenosine (m⁶A) modification is a key mechanism to regulate the tumorigenesis of prostate cancer (PC). However, the function of Vir Like M6A Methyltransferase Associated (VIRMA), an m⁶A writer, in PC remains further explored. Therefore, the objective of this study is to verify the function and mechanism of VIRMA in PC via non-SMC Element 2 (NSMCE2) and reactive oxygen species (ROS).

Methods: The effects of VIRMA and NSMCE2 on PC cell malignancy were detected via a series of cell experiments. qRT-PCR, MeRIP, mRNA stability, and RIP assays were performed to further verify the regulatory mechanism of VIRMA on NSMCE2. ROS levels, oxidative stress markers, and cell apoptosis were detected by DCFH-DA, commercial kits, and flow cytometry methods. In vivo assays were performed to confirm the effects of the VIRMA/NSMCE2 axis on tumor growth.

Results: VIRMA and NSMCE2 were both upregulated in PC samples, and VIRMA expression was positively correlated to NSMCE2 expression in PC samples. After silencing VIRMA in PC cells, the abilities of proliferation, migration, and invasion were impaired. However, the anti-tumor effects of VIRMA knockdown on PC cell malignancy in vitro and tumor growth in vivo could be reversed by NSMCE2 overexpression. In addition, VIRMA mediated m⁶A modification of NSMCE2 to enhance the mRNA stability of NSMCE2 via an IGF2BP1-dependent manner, thereby reducing ROS levels and the apoptosis rate.

Conclusion: VIRMA accelerates PC tumorigenesis by inducing the m⁶A modification of NSMCE2 to eliminate the generation of ROS.