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The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway

BACKGROUND: Many studies have reported that N6-methyladenosine (m6A) modification plays a critical role in the epigenetic regulation of organisms and especially in the pathogenesis of malignant diseases. However, m6A research has mainly focused on methyltransferase activity mediated by METTL3, and f...

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Autores principales: Xie, Fuming, Zheng, Yao, Fu, Wen, Chi, Bojing, Wang, Xianxing, Zhang, Junfeng, Gu, Jianyou, Yin, Jingyang, Zhou, Qiang, Guo, Shixiang, Cai, Lei, Yang, Jiali, Liu, Songsong, Wang, Huaizhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10166879/
https://www.ncbi.nlm.nih.gov/pubmed/37182151
http://dx.doi.org/10.3389/fonc.2023.1138238
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author Xie, Fuming
Zheng, Yao
Fu, Wen
Chi, Bojing
Wang, Xianxing
Zhang, Junfeng
Gu, Jianyou
Yin, Jingyang
Zhou, Qiang
Guo, Shixiang
Cai, Lei
Yang, Jiali
Liu, Songsong
Wang, Huaizhi
author_facet Xie, Fuming
Zheng, Yao
Fu, Wen
Chi, Bojing
Wang, Xianxing
Zhang, Junfeng
Gu, Jianyou
Yin, Jingyang
Zhou, Qiang
Guo, Shixiang
Cai, Lei
Yang, Jiali
Liu, Songsong
Wang, Huaizhi
author_sort Xie, Fuming
collection PubMed
description BACKGROUND: Many studies have reported that N6-methyladenosine (m6A) modification plays a critical role in the epigenetic regulation of organisms and especially in the pathogenesis of malignant diseases. However, m6A research has mainly focused on methyltransferase activity mediated by METTL3, and few studies have focused on METTL16. The aim of this study was to investigate the mechanism of METTL16, which mediates m6A modification, and its role in pancreatic adenocarcinoma (PDAC) cell proliferation. METHODS: Clinicopathologic and survival data were retrospectively collected from 175 PDAC patients from multiple clinical centers to detect the expression of METTL16. CCK-8, cell cycle, EdU and xenograft mouse model experiments were used to evaluate the proliferation effect of METTL16. Potential downstream pathways and mechanisms were explored via RNA sequencing, m6A sequencing, and bioinformatic analyses. Regulatory mechanisms were studied through methyltransferase inhibition, RIP, MeRIP‒qPCR assays. RESULTS: We found that METTL16 expression was markedly downregulated in PDAC, and multivariate Cox regression analyses revealed that METTL16 was a protective factor for PDAC patients. We also demonstrated that METTL16 overexpression inhibited PDAC cell proliferation. Furthermore, we identified a METTL16-p21 signaling axis, with downregulation of METTL16 resulting in inhibition of CDKN1A (p21). Additionally, METTL16 silencing and overexpression experiments highlighted m6A modification alterations in PDAC. CONCLUSIONS: METTL16 plays a tumor-suppressive role and suppresses PDAC cell proliferation through the p21 pathway by mediating m6A modification. METTL16 may be a novel marker of PDAC carcinogenesis and target for the treatment of PDAC.
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spelling pubmed-101668792023-05-10 The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway Xie, Fuming Zheng, Yao Fu, Wen Chi, Bojing Wang, Xianxing Zhang, Junfeng Gu, Jianyou Yin, Jingyang Zhou, Qiang Guo, Shixiang Cai, Lei Yang, Jiali Liu, Songsong Wang, Huaizhi Front Oncol Oncology BACKGROUND: Many studies have reported that N6-methyladenosine (m6A) modification plays a critical role in the epigenetic regulation of organisms and especially in the pathogenesis of malignant diseases. However, m6A research has mainly focused on methyltransferase activity mediated by METTL3, and few studies have focused on METTL16. The aim of this study was to investigate the mechanism of METTL16, which mediates m6A modification, and its role in pancreatic adenocarcinoma (PDAC) cell proliferation. METHODS: Clinicopathologic and survival data were retrospectively collected from 175 PDAC patients from multiple clinical centers to detect the expression of METTL16. CCK-8, cell cycle, EdU and xenograft mouse model experiments were used to evaluate the proliferation effect of METTL16. Potential downstream pathways and mechanisms were explored via RNA sequencing, m6A sequencing, and bioinformatic analyses. Regulatory mechanisms were studied through methyltransferase inhibition, RIP, MeRIP‒qPCR assays. RESULTS: We found that METTL16 expression was markedly downregulated in PDAC, and multivariate Cox regression analyses revealed that METTL16 was a protective factor for PDAC patients. We also demonstrated that METTL16 overexpression inhibited PDAC cell proliferation. Furthermore, we identified a METTL16-p21 signaling axis, with downregulation of METTL16 resulting in inhibition of CDKN1A (p21). Additionally, METTL16 silencing and overexpression experiments highlighted m6A modification alterations in PDAC. CONCLUSIONS: METTL16 plays a tumor-suppressive role and suppresses PDAC cell proliferation through the p21 pathway by mediating m6A modification. METTL16 may be a novel marker of PDAC carcinogenesis and target for the treatment of PDAC. Frontiers Media S.A. 2023-04-25 /pmc/articles/PMC10166879/ /pubmed/37182151 http://dx.doi.org/10.3389/fonc.2023.1138238 Text en Copyright © 2023 Xie, Zheng, Fu, Chi, Wang, Zhang, Gu, Yin, Zhou, Guo, Cai, Yang, Liu and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Xie, Fuming
Zheng, Yao
Fu, Wen
Chi, Bojing
Wang, Xianxing
Zhang, Junfeng
Gu, Jianyou
Yin, Jingyang
Zhou, Qiang
Guo, Shixiang
Cai, Lei
Yang, Jiali
Liu, Songsong
Wang, Huaizhi
The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
title The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
title_full The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
title_fullStr The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
title_full_unstemmed The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
title_short The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
title_sort m6a methyltransferase mettl16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10166879/
https://www.ncbi.nlm.nih.gov/pubmed/37182151
http://dx.doi.org/10.3389/fonc.2023.1138238
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