LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

BackgroundLong noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target.MethodsWe screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact withLINRIS(Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells withLINRISinhibited were tested in vitro and in vivo.ResultsLINRISwas upregulated in CRC tissues from patients with poor overall survival (OS), andLINRISinhibition led to the impaired CRC cell line growth. Moreover, knockdown ofLINRISresulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’.LINRISblocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown ofLINRISattenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription ofLINRIScould be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition ofLINRISsuppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.ConclusionLINRISis an independent prognostic biomarker for CRC. TheLINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.