Methionine metabolism and the NOP2 methyltransferase are essential for MYC-Driven liver tumorigenesis

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in developed nations.^1,2 The MYC oncogene or its paralogs are frequently amplified or overexpressed in subtypes of cancer associated with stem cell-like features and worse clinical outcomes,^3,4 including in liver cancer.⁵ Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent, with markedly diminished tumor growth when mice are fed a methionine low diet. While RAS-driven liver cancer was resistant to a low methionine diet. S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues cell proliferation following methionine depletion, suggesting that methylation processes are especially critical in the context of MYC high tumor cells. Heavy isotope methionine tracing in MYC high cells identified increased levels of m5C nucleotides. We found NOP2, an rRNA m5C-methyltransferase, was regulated by both MYC overexpression and methionine abundance linking the two processes. Methionine depletion reduced methylation of multiple 28S rRNA residues as did NOP2 knockdown. Depletion of NOP2 selectively inhibited MYC liver cancer cell proliferation and <i>in vivo</i> tumor growth. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and the rRNA methyltransferase NOP2 may serve as a new therapeutic target in liver cancer.