The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA’s specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which mightprovide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.

Aberrant expression of long noncoding RNAs (lncRNAs) has been involved in progression of various human tumors including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC has not fully explained. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. Our study showed that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and higher Lnc-PLA2G4A-4 was remarkably related to tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitate lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitated miR-23b-3p’s target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reversed cell phenotypes caused by Lnc-PLA2G4A-4 in HCC and suppress the expression of versican by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes the progression of HCC via targeting miR-23b-3p/versican axis, which might be a potential biomarker and therapeutic target for HCC.

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