LARP6 induces sphingolipid metabolism imbalance to suppress colorectal cancer metastasis by post-transcriptional regulation

Abstract RNA-binding proteins (RBPs) are key drivers for post-transcriptional mechanisms of cancer progression. In this study, we found that LARP6 expression is downregulated in colorectal cancer (CRC) and correlates with patients' overall survival and relapse-free survival. Altered LARP6 expression influenced invasion and metastasis ability of CRC cells. Mechanistically, by post-transcriptional regulation on ZNF267 expression, LARP6 inhibits SGMS2-mediated sphingomyelin synthesis, resulting in sphingolipid homeostasis imbalance. Meanwhile, we also found that LARP6 enhances autophagy activity of CRC cells, and more interestingly, this enhancement is at least partially dependent on inhibition of SGMS2-mediated sphingomyelin synthesis. In conclusion, our study elucidates a novel mechanism by which LARP6/ZNF267/SGMS2 axis suppresses CRC metastasis, and provides a potential therapeutic target for CRC.