METTL3-Mediated m ⁶ A Modification of lncRNA MALAT1 Facilitates Prostate Cancer Growth by Activation of PI3K/AKT Signaling

Abstract

Accumulating data show that N6-methyladenosine (m 6 A) methyltransferase METTL3 and long noncoding RNA MALAT1 act pivotal roles in multiple malignancies including prostate cancer (PCa). However, the role and molecular mechanism underlying METTL3-mediated m 6 A modification of MALAT1 in PCa remain undocumented. The association of METTL3 and MALAT1 expression with clinicopathological characteristics and prognosis in patients with PCa was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and public The Cancer Genome Atlas (TCGA) dataset. The in vitro and in vivo experiments were executed to investigate the role of METTL3 in PCa. m 6 A dot blot, methylated RNA immunoprecipitation (MeRIP), RIP, and qRT-PCR assays were employed to observe METTL3-mediated m 6 A modification of MALAT1. The effects of METTL3 on MALAT1-mediated PI3K/AKT pathway were assessed by Western blot analysis. As a result, we found that METTL3 was significantly upregulated in PCa tissues and high expression of METTL3 was associated with Gleason score and tumor recurrence in patients with PCa. Knockdown of METTL3 markedly repressed growth and invasion of PCa cells in vitro and in vivo, whereas ectopic expression of METTL3 showed the opposite effects. Moreover, knockdown of METTL3 decreased the total m 6 A levels of PCa cells as well as the MALAT1 m 6 A levels, leading to reduced MALAT1 expression. Overexpression of MALAT1 reversed METTL3 knockdown-induced antitumor effects and PI3K/AKT signaling inactivation. MALAT1 harbored a positive correlation with METTL3 expression and tumor recurrence in PCa. In conclusion, our findings demonstrate that METTL3-mediated m 6 A modification of lncRNA MALAT1 promotes growth and invasion of PCa cells by activating PI3K/AKT signaling.