m6A RNA methyltransferase METTL16 induces Cr(VI) carcinogenesis and lung cancer development through glutamine biosynthesis and GLUL expression

Hexavalent chromium [Cr(VI)] exposure increases the risk of cancer occurrence. This study found that the levels of an atypical methyltransferase, METTL16 were greatly upregulated in the cells, and mouse tissues with Cr(VI) exposure, and played a critical role in cell proliferation and tumor growth induced by Cr(VI). Similarly, we found METTL16 was upregulated in various human cancer tissues. To understand mechanism of METTL16 in inducing carcinogenesis and cancer development, we identified that glutamate-ammonia ligase (GLUL) as the METTL16 functional target for regulating glutamine metabolism and tumorigenesis induced by Cr(VI) exposure. We demonstrated that METTL16 promoted GLUL expression in a m6A-dependent manner. Furthermore, METTL16 methylated the specific stem-loop structure of GLUL transcript, thereby increased the recognition and splicing of pre-GLUL RNA modified site by m6A reader YTHDC1, which ultimately accelerated the production of mature GLUL mRNA. Animal model of Cr(VI) exposure further confirmed that the expression levels of METTL16 and GLUL were both significantly induced in vivo, and there had a significant positive correlation between METTL16 and GLUL levels. Furthermore, we found that YTHDC1 was also important in inducing GLUL expression, and MYC was the upstream mediator of METTL16 to increase its transcriptional activation. Our study revealed new mechanism of metal carcinogenesis and cancer development.