METTL3 promotes prostatic hyperplasia by regulating PTEN expression in an m6A-YTHDF2-dependent manner

Abstract

Uncontrolled epithelial cell proliferation in the prostate transition zone and the hyper-accumulation of mesenchymal-like cells derived from the epithelial-mesenchymal transition (EMT) of prostatic epithelium are two key processes in benign prostatic hyperplasia (BPH). m6A RNA modification affects multiple cellular processes, including cell proliferation, apoptosis, and differentiation. In this study, the aberrant up-regulation of methylase METTL3 in BPH samples suggests its potential role in BPH development. Elevated m6A modification in the prostate of the BPH rat was partially reduced by METTL3 knockdown. METTL3 knockdown also partially reduced the prostatic epithelial thickness and prostate weight, significantly improved the histological features of the prostate, inhibited epithelial proliferation and EMT, and promoted apoptosis. In vitro, METTL3 knockdown decreased TGF-β-stimulated BPH-1 cell proliferation, m6A modification, and EMT, whereas promoted cell apoptosis. METTL3 increased the m6A modification of PTEN and inhibited its expression through the reading protein YTHDF2. PTEN knockdown aggravated the molecular, cellular, and pathological alterations in the prostate of BPH rats and amplified TGF-β-induced changes in BPH-1 cells. More importantly, PTEN knockdown partially abolished the improving effects of METTL3 knockdown both in vivo and in vitro. In conclusion, the level of m6A modification is elevated in BPH; the METTL3/YTHDF2/PTEN axis disturbs the balance between epithelial proliferation and apoptosis, promotes EMT, and accelerates BPH development in an m6A modification-related manner.

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia

“…A comprehensive understanding of the intricate processes underlying proliferative nodules holds immense clinical significance in terms of identifying novel therapeutic targets for BPH. Previous studies have indicated that, apart from LE cells which are targeted by 5-ARIs, other cell types within the prostate have been implicated in this pathogenesis [ 10 , 12 , 41 – 43 ], highlighting their potential as therapeutic targets for BPH. However, due to technological limitations, their contributions have yet to be validated through in vivo investigations conducted on patients with BPH.…”

“…Although several cellular processes have been reported to be involved in BPH initiation and development, Its specific mechanism is largely unknown. The contribution of androgen response [ 6 , 7 ], hypoxia [ 8 , 9 ], epithelial-mesenchymal transition (EMT) [ 10 – 12 ], etc. in prostatic epithelium to the development of BPH has been acknowledged, highlighting the crucial role of epithelial cells in proliferative nodular formation.…”

LncRNA RARA-AS1 could serve as a novel prognostic biomarker in pan-cancer and promote proliferation and migration in glioblastoma

“…METTL3, an m6A methyltransferase, has oncogenic function in several human cancer 32 . By reducing METTL3 expression, cancer cells can be less capable of migrating, invading, and undergoing epithelial-mesenchymal transitions 33 , 34 . YTHDF1 is highly expressed in colon cancer and knocking it down significantly inhibits the tumorigenicity of CRC cells in vitro 35 .…”

Methyltransferase-like proteins in cancer biology and potential therapeutic targeting

“…METTL3/14 complex mediates the m6A methylation of NAP1L2 mRNA, and LncRNA NAP1L6 recruits HNRNPC to the m6A sites of NAP1L2, promoting NAP1L2 mRNA stabilization, inducing cell migration, invasion, and enhancing EMT function [ 184 ]. METTL3 inhibits PTEN expression through the m6A-YTHDF2 modality and promotes prostate hyperplasia [ 185 ].…”