N6-Methyladenosine Promotes the Transcription of c-Src Kinase via IRF1 to Facilitate the Proliferation of Liver Cancer

Expression of mRNA is widely regulated by N6-methyladenosine (m⁶A). An increasing number of studies have shown that m⁶A methylation, facilitated by methyltransferase 3 (METTL3), is crucial in the progression of tumors. Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer. However, the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.

The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database, and was further demonstrated by Western blot and RT-qPCR. The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays. The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation (RIP)-qPCR.

We demonstrated that c-Src kinase promoted liver cancer development, and the expression of SRC (encodes c-Src kinase) was positively correlated with METTL3 in liver cancer cases. We showed that SRC mRNA could be m⁶A-modified, and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1 (IRF1). We revealed that IRF1, the expression of which was positively regulated by METTL3, was a novel transcription factor of c-Src. Lastly, The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation, as evidenced by our experimental data.

Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.