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

作者全名："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"

作者地址："[Xie, Fuming; Fu, Wen; Yin, Jingyang; Wang, Huaizhi] Chongqing Med Univ, Univ Chinese Acad Sci UCAS, Chongqing Sch, Chongqing, Peoples R China; [Xie, Fuming; Fu, Wen; Yin, Jingyang; Wang, Huaizhi] Chinese Acad Sci, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China; [Xie, Fuming; Fu, Wen; Yin, Jingyang; Wang, Huaizhi] Univ Chinese Acad Sci UCAS, Chongqing Sch, Chongqing, Peoples R China; [Xie, Fuming; Zheng, Yao; Fu, Wen; Chi, Bojing; Wang, Xianxing; Zhang, Junfeng; Gu, Jianyou; Yin, Jingyang; Zhou, Qiang; Guo, Shixiang; Cai, Lei; Yang, Jiali; Wang, Huaizhi] Univ Chinese Acad Sci UCAS Chongqing, Chongqing Gen Hosp, Inst Hepatopancreatobiliary Surg, Chongqing, Peoples R China; [Zheng, Yao; Wang, Xianxing; Zhou, Qiang; Guo, Shixiang; Yang, Jiali; Wang, Huaizhi] Chongqing Gen Hosp, Chongqing Key Lab Intelligent Med Engn Hepatopancr, Chongqing, Peoples R China; [Chi, Bojing] Univ Chinese Acad Sci UCAS, Savaid Med Sch, Beijing, Peoples R China; [Liu, Songsong] China PLA Gen Hosp, Hainan Hosp Peoples Liberat Army, Dept Hepatobiliary Surg, Sanya, Peoples R China"

通信作者："Wang, HZ (通讯作者)，Chongqing Med Univ, Univ Chinese Acad Sci UCAS, Chongqing Sch, Chongqing, Peoples R China.; Wang, HZ (通讯作者)，Chinese Acad Sci, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China.; Wang, HZ (通讯作者)，Univ Chinese Acad Sci UCAS, Chongqing Sch, Chongqing, Peoples R China.; Yang, JL; Wang, HZ (通讯作者)，Univ Chinese Acad Sci UCAS Chongqing, Chongqing Gen Hosp, Inst Hepatopancreatobiliary Surg, Chongqing, Peoples R China.; Yang, JL; Wang, HZ (通讯作者)，Chongqing Gen Hosp, Chongqing Key Lab Intelligent Med Engn Hepatopancr, Chongqing, Peoples R China.; Liu, SS (通讯作者)，China PLA Gen Hosp, Hainan Hosp Peoples Liberat Army, Dept Hepatobiliary Surg, Sanya, Peoples R China."

来源：FRONTIERS IN ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000982979900001

JCR分区：Q2

影响因子：4.7

年份：2023

卷号：13

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：pancreatic adenocarcinoma; METTL16; m6A; p21; cell proliferation

摘要："BackgroundMany 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. MethodsClinicopathologic 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. ResultsWe 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. ConclusionsMETTL16 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."

基金机构："National Natural Science Foundation of China [82072723, 82103249]; Chongqing Natural Science Foundation (Post-Doctoral Fund) [cstc2021jcyj-bsh0234]; Special Key Project of Technology Innovation and Application Development in Chongqing [cstc2020jscx-sbqwX0022]; Chongqing Postgraduate Research Innovation Project [CYB20169]"

基金资助正文：Funding This work was supported by the following grants: the National Natural Science Foundation of China (NO. 82072723 and NO. 82103249); Chongqing Natural Science Foundation (Post-Doctoral Fund) (NO. cstc2021jcyj-bsh0234); the Special Key Project of Technology Innovation and Application Development in Chongqing (NO. cstc2020jscx-sbqwX0022); Chongqing Postgraduate Research Innovation Project (NO. CYB20169).