METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination

Danyang Shen; Lifeng Ding; Zeyi Lu; Ruyue Wang; Chenhao Yu; Huan Wang; Qiming Zheng; Xuliang Wang; Wanjiang Xu; Haifeng Yu; Liwei Xu; Mingchao Wang; Shicheng Yu; Shibin Zhu; Jun Qian; Liqun Xia; Gonghui Li

doi:10.1016/j.omtn.2021.12.024

METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination

Mol Ther Nucleic Acids. 2021 Dec 17:27:547-561. doi: 10.1016/j.omtn.2021.12.024. eCollection 2022 Mar 8.

Authors

Danyang Shen^{1

2}, Lifeng Ding¹, Zeyi Lu¹, Ruyue Wang¹, Chenhao Yu¹, Huan Wang¹, Qiming Zheng¹, Xuliang Wang¹, Wanjiang Xu¹, Haifeng Yu¹, Liwei Xu¹, Mingchao Wang¹, Shicheng Yu¹, Shibin Zhu¹, Jun Qian³, Liqun Xia¹, Gonghui Li¹

Affiliations

¹ Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
² Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
³ State Key Laboratory of Modern Optical Instrumentations, Centre for Optical and Electromagnetic Research, College of Optical Science and Engineering, Zhejiang University, Hangzhou 310058, China.

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m⁶A) is implicated in various stages of cancer development. However, a thorough understanding of m⁶A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m⁶A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m⁶A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m⁶A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m⁶A and lncRNA in ccRCC for the first time.

Keywords: ESRP2; Lnc-LSG1; METTL14; N6-methyladenosine; YTHDC1; clear cell renal cell carcinoma.