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

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. [Display omitted] N6-Methyladenosine (m6A) is the most common RNA modification and implicated in various stages of cancer development. METTL14 is an important methyltransferase of m6A. For the first time, we provide insights into the function and mechanism of m6A-modified lncRNA in ccRCC and identify a “METTL14-YTHDC1-Lnc-LSG1” regulation axis in ccRCC progression.