Hypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis

Summary: Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers. The mechanisms by which intratumoral hypoxia regulates metastasis are not fully understood. Our study identifies a downregulation of Lnc-CSMD1-7 in hepatocellular carcinoma (HCC) and correlated with poor prognosis of HCC patients. Lnc-CSMD1-7 negatively regulated HCC cell migration and invasion in vitro and suppressed lung metastasis in vivo. Mechanistically, Lnc-CSMD1-7 directly binds to RBFOX2, thereby affecting RBFOX2-regulated alternative splicing in epithelial and mesenchymal-specific events. More importantly, hypoxic microenvironment and m6A methylation mediate the downregulation of Lnc-CSMD1-7 expression. Specifically, hypoxia transcriptionally upregulates the expression of the m6A methyltransferase METTL16 via HIF-1α, and METTL16 directly binds to Lnc-CSMD1-7 and downregulates the RNA stability of Lnc-CSMD1-7 via m6A methylation, ultimately promoting HCC metastasis. Our findings highlight the regulatory function of the METTL16/Lnc-CSMD1-7/RBFOX2 axis in modulating hypoxia-induced HCC progression, which may provide potential prognostic and therapeutic targets for HCC treatment.