LARP6 suppresses colorectal cancer progression through ZNF267/SGMS2-mediated imbalance of sphingomyelin synthesis

Abstract

AbstractBackgroundWith increasing incidence and mortality, colorectal cancer (CRC) seriously endangers human health.LARP6, a member of La-related protein (LARP) family, is a RNA binding protein and probably associates with CRC progression, but its specific roles and mechanisms in CRC still remain unknown.MethodQuantitative real-time PCR (qPCR), western blot, and immunohistochemistry were employed to examine LARP6 expression in CRC tissues. Using the stableLARP6overexpression or interference CRC cell lines, the effect of LARP6 on CRC progression were evaluated. High-throughput RNA immunoprecipitation sequencing (RIP-seq) and a series of relevant experiments were conducted to explain how LARP6 functions. SPSS software was used for statistical analysis.ResultIn this study, we found thatLARP6expression is downregulated in CRC and correlates with patients’ overall survival and relapse-free survival. Furthermore, altered LARP6 expression influences CRC cells invasion and metastasis. Mechanically, we discovered that LARP6 bindZNF267mRNA and regulated its stability and translation. LARP6 inhibited expression ofSGMS2, a downstream target of ZNF267, resulting in ceramide and sphingomyelin imbalance in CRC cells. Interestingly, LARP6 also enhances autophagy activity of CRC cells, and the effect was at least partially determined by the inhibition of SGMS2-mediated sphingomyelin synthesis.ConclusionOur study showed howLARP6/ZNF267/SGMS2axis influence CRC progression, which contributes to further understanding of the molecular mechanisms underlying CRC development.