LINC01852 inhibits tumorigenesis and chemoresistance in colorectal cancer by regulating SRSF5-mediated PKM alternative splicing

Abstract Background Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide, and chemoresistance is a major obstacle in the treatment of this disease. Despite advances in therapy, the molecular mechanism underlying chemoresistance in CRC is not fully understood. Recent studies have implicated the key roles of long noncoding RNAs (lncRNAs) in the regulation of CRC chemoresistance. Methods In this study, we investigated the role of lncRNA LINC01852 in CRC chemoresistance. The expression of LINC01852 was evaluated in multiple CRC cohorts using quantitative reverse transcription PCR. We conducted in vitro and in vivo functional experiments using cell culture and mouse models. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of LINC01852 in CRC. Results Our findings a lncRNA with tumor-inhibiting properties, LINC01852, that is downregulated in CRC and inhibits cell proliferation and chemoresistance both in vitro and in vivo. Further mechanistic investigations revealed that LINC01852 enhances TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated PKM alternative splicing and thereby decreasing the production of PKM2. Overexpression of LINC01852 causes a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC by inhibiting PKM2-mediated glycolysis. Conclusions Our results demonstrate that LINC01852 plays an important role in repressing CRC malignancy and chemoresistance by regulating SRSF5-mediated PKM alternative splicing, and that targeting the LINC01852/TRIM72/SRSF5/PKM2 signaling axis may represent a potential therapeutic strategy for the treatment of CRC.