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

Fuming Xie; Yao Zheng; Wen Fu; Bojing Chi; Xianxing Wang; Junfeng Zhang; Jianyou Gu; Jingyang Yin; Qiang Zhou; Shixiang Guo; Lei Cai; Jiali Yang; Songsong Liu; Huaizhi Wang

doi:10.3389/fonc.2023.1138238

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

Front Oncol. 2023 Apr 25:13:1138238. doi: 10.3389/fonc.2023.1138238. eCollection 2023.

Authors

Fuming Xie^{1

2

3

4}, Yao Zheng^{4

5}, Wen Fu^{1

2

3

4}, Bojing Chi^{4

6}, Xianxing Wang^{4

5}, Junfeng Zhang⁴, Jianyou Gu⁴, Jingyang Yin^{1

2

3

4}, Qiang Zhou^{4

5}, Shixiang Guo^{4

5}, Lei Cai⁴, Jiali Yang^{4

5}, Songsong Liu⁷, Huaizhi Wang^{1

2

3

4

5}

Affiliations

¹ University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, China.
² Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences (CAS), Chongqing, China.
³ Chongqing School, University of Chinese Academy of Sciences (UCAS), Chongqing, China.
⁴ Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences (UCAS Chongqing), Chongqing, China.
⁵ Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing General Hospital, Chongqing, China.
⁶ Savaid Medical School, University of Chinese Academy of Sciences (UCAS), Beijing, China.
⁷ Department of Hepatobiliary Surgery, Hainan Hospital of People's Liberation Army of China (PLA) General Hospital, Sanya, China.

Abstract

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.

Keywords: METTL16; cell proliferation; m6A; p21; pancreatic adenocarcinoma.

Grants and 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).