METTL3-Mediated m⁶A Modification of lncRNA MALAT1 Facilitates Prostate Cancer Growth by Activation of PI3K/AKT Signaling

Abstract

Accumulating data show that N6-methyladenosine (m6A) 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 m6A 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. m6A dot blot, methylated RNA immunoprecipitation (MeRIP), RIP, and qRT-PCR assays were employed to observe METTL3-mediated m6A 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 m6A levels of PCa cells as well as the MALAT1 m6A 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 m6A modification of lncRNA MALAT1 promotes growth and invasion of PCa cells by activating PI3K/AKT signaling.

METTL3‐mediated m6A modification of pri‐miR‐148a‐3p affects prostate cancer progression by regulating TXNIP

“…The high expression of METTL3 has been discovered in PCa previously. 39 RT-qPCR and Western blotting found that METTL3 expression in PCa cell lines (LNCaP, DU145, LAPC-4, VCaP) was observably elevated relative to prostate epithelial cells RWPE-1 (all p < .05) (Figure 1A,B), which was the highest in DU145 cells. Therefore, cell line DU145 was selected for subsequent studies.…”

The emerging roles and mechanism of N6-methyladenosine (m6A) modifications in urologic tumours progression

“…As a lncRNA, the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is oncogenic in numerous tumours progressions ( Fan et al, 2014 ; Jen et al, 2017 ). Yuan et al ( Mao et al, 2022 ) confirmed that METTL3 could upregulate the m 6 A level of LncRNA-MALAT1, which activates the PI3K/AKT signaling pathway and promotes the growth and invasion of PCa. The molecular mechanisms of m 6 A methylation modifications in tumour cells have recently been studied.…”

“…Studies of writers on PCa have primarily focused on the regulatory component METTL3. Recent studies have indicated that METTL3 plays an oncogenic role in PCa ( Cai et al, 2019 ; Li et al, 2020a ; Li et al, 2020b ; Ma et al, 2020 ; Yuan et al, 2020 ; Chen et al, 2021a ; Ma et al, 2021 ; Liu et al, 2022a ; Wang et al, 2022a ; Mao et al, 2022 ; Chen et al, 2023 ). Only one study has suggested that it is a carcinogenic tumour suppressor ( Jia et al, 2022 ).…”

“…Recent studies have depicted that FTO can also regulate the progression of BC cells by affecting the metabolism of miRNAs and lncRNAs. A previous section elucidated that Lnc-MALAT1 could promote progression in the PCa via an m 6 A-dependent mechanism ( Mao et al, 2022 ). According to Tao et al ( Tao et al, 2021 ), FTO can facilitate suppression of m 6 A modification of the Lnc-Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) 5′-end and thus prevents YTHDF2’s degradation of MALAT1 mRNA.…”

Role of N6‑methyladenosine in the pathogenesis, diagnosis and treatment of prostate cancer (Review)

“…Studies have linked the lncRNA MALAT1 and the m 6 A methyltransferase METTL3 to malignancy progression in PCa. The m 6 A modification of lncRNA MALAT1 can be mediated by METTL3, thereby activating the PI3K/AKT signaling pathway, which promotes malignancy progression in PCa ( 90 ). Elevated levels of the lncRNA nuclear enriched abundant transcript (NEAT)1-1 recognize and activate the activity of CYCLOINL1 and form a different complex with extreme levels of CDK19 in PCa, which ultimately acts on the promoter Runt-related transcription factor 2 (RUNX2).…”