CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3

Lei Yang,Weidong Gan,Dongmei Li,Zhenhao Yang,Wenliang Ma,Yanwen Lu,Yi Chen,Ning Liu

doi:10.1186/s12943-022-01497-w

Abstract

BackgroundFunctions of CircMET (hsa_circ_0082002) which is a circular RNA and derived from MET gene remain understood incompletely. In the present study, Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (NONO-TFE3 tRCC) with up-regulated CircMET was employed to investigate its mechanism in cancer progression and post-transcriptional regulation.MethodsFISH and real-time PCR were performed to explore the expression and localization circMET in NONO-TFE3 tRCC tissues and cells. The functions of circMET in tRCC were investigated by proliferation analysis, EdU staining, colony and sphere formation assay. The regulatory mechanisms among circMET, CDKN2A and SMAD3 were investigated by luciferase assay, RNA immunoprecipitation, RNA pulldown and targeted RNA demethylation system.ResultsThe expression of circMET was upregulated by NONO-TFE3 fusion in NONO-TFE3 tRCC tissues and cells, and overexpression of circMET significantly promoted the growth of NONO-TFE3 tRCC. Mechanistic studies revealed that circMET was delivered to cytosol by YTHDC1 in N6-methyladenosine (m6A)-depend manner. CircMET enhances mRNA decay of CDKN2A by direct interaction and recruitment of YTHDF2. Meanwhile, circMET competitively absorbed miR-1197 and prevented those from SMAD3 mRNA.ConclusionsCircMET promotes the development of NONO-TFE3 tRCC, and the regulation to both CDKN2A and SMAD3 of circMET was revealed. CircMET has the potential to serve as a novel target for the molecular therapy of NONO-TFE3 tRCC as well as the other cancer with high-expressing circMET.

Highlights

Functions of CircMET which is a circular RNA and derived from MET gene remain understood incompletely
CircMET expression is significantly increased in Non-POU domain containing octamer binding (NONO)‐transcript factor E3 (TFE3) tRCCIn our previous study, MET was identified as a potential target gene of NONO-TFE3 by Chromatin immunoprecipitation (ChIP)-seq
To explore if the expression of circRNAs derived from MET gene is correlated with NONO-TFE3 Translocation renal cell carcinoma (tRCC), real-time PCR was performed to determine the expression of them

Summary

Introduction

Functions of CircMET (hsa_circ_0082002) which is a circular RNA and derived from MET gene remain understood incompletely. Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (NONOTFE3 tRCC) with up-regulated CircMET was employed to investigate its mechanism in cancer progression and posttranscriptional regulation. Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC), as an independent subset of RCC in the 2016 WHO classification [1], is characterized with poor prognosis of patients caused by high expression of transcript factor E3 (TFE3) fusion gene. An increasing number of researches suggest that these high-expressed TFE3-fusion proteins can function as a major driver of cancer by regulating directly or indirectly downstream target genes. The NONO-TFE3 fusion maintains original functions of wild type TFE3, such as upregulation of lysosomal biogenesis genes via binding to promoter region [6]. NONO-TFE3 fusion regulates mitochondrial biosynthesis and metabolism through upregulation of nuclear respiratory factor 1 [7] and hypoxic adaptation via inducing the expression of hypoxia inducible factor 1 subunit alpha [8], which facilitate tumor progression of NONO-TFE3 tRCC

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Results

Discussion

Conclusion