Rewiring of de novo serine synthesis supports tumorigenesis under deficiency of TET2.

backgroundTen-eleven translocation 2 (TET2) is initially identified as a mammalian DNA dioxygenase to orchestrate expression of numerous genes and diverse interplays of physiological and pathological processes. Beyond its canonical role, the moonlight functions of TET2 have been gradually uncovered.

methodsRNA-seq, qPCR and western blot are employed to validate expression of genes. ChIP and RIP analyses are conducted to test the enrichment of genes. Stable isotope labelled glucose is utilized to analyze the metabolic flux. Xenograft analysis is performed to explore growth of tumour in vivo.

resultsTET2 binds to and oxidizes mRNA 5-methylcytosine (m5C) of the transcription factors ATF3 and ATF4, thereby enhancing mRNAs degradation. Deficiency of TET2 rewires de novo serine synthesis and the viability of hepatocellular carcinoma (HCC) cells. Both ATF3 and ATF4 are required to sustain transcription of de novo serine synthesis enzymes and the associated metabolic reprogramming under TET2 loss. Ultimately, ATF3 collaborates with ATF4 to contribute to growth of tumours lack of TET2. Deficiency of TET2 sensitizes HCC tumours to serine restriction.

conclusionsOur findings not only elucidate a heretofore unrecognized mechanism of transcriptional suppression of de novo serine synthesis enzymes, but also propose a targetable vulnerability of HCC tumours.