Phosphorylation of c-Myc at Ser62 via the protein kinase activity of acetaldehyde dehydrogenase 18A1 promotes tumor growth.

The oncoprotein c-Myc is a prominent target in cancer therapy and modulating its stability is a promising potential treatment strategy. Phosphorylation at Ser62 is the primary mechanism by which c-Myc degradation is suppressed, which extends its half-life. Consequently, identifying kinases that regulate the phosphorylation of c-Myc at Ser62 may pave the way for novel intervention strategies. In this study, we revealed that acetaldehyde dehydrogenase 18A1 (ALDH18A1), a key enzyme in glutamate-proline metabolism, acts as a protein kinase through its γ-glutamate kinase (γ-GK) domain, which mediates the phosphorylation of the Ser62 site of c-Myc and suppresses its degradation. In turn, stabilized c-Myc directly increases the transcription of ALDH18A1. This positive feedback loop sustains the mutual high expression of both proteins, which promotes the development of various tumors. Thonzonium bromide (TB), a small-molecule inhibitor screened from a Food and Drug Administration-approved drug library, was found to block ALDH18A1-mediated phosphorylation of c-Myc at Ser62 and attenuate tumor progression in preclinical models. Overall, these findings reveal the therapeutic potential of inhibiting the ALDH18A1-MYC regulatory circuit in human cancers.