Phosphorylated SHMT2 Regulates Oncogenesis Through m6A Modification in Lung Adenocarcinoma

Targeting cancer‐specific metabolic processes is a promising therapeutic strategy. Here, this work uses a compound library that directly inhibits metabolic enzymes to screen the potential metabolic targets in lung adenocarcinoma (LUAD). SHIN1, the specific inhibitor of serine hydroxymethyltransferase 1/2 (SHMT1/2), has a highly specific inhibitory effect on LUAD cells, and this effect depends mainly on the overexpression of SHMT2. This work clarifies that mitogen‐activated protein kinase 1 (MAPK1)‐mediated phosphorylation at Ser90 is the key mechanism underlying SHMT2 upregulation in LUAD and that this phosphorylation stabilizes SHMT2 by reducing STIP1 homology and U‐box containing protein 1 (STUB1)‐mediated ubiquitination and degradation. SHMT2‐Ser90 dephosphorylation decreases S‐adenosylmethionine levels in LUAD cells, resulting in reduced N6‐methyladenosine (m6A) levels in global RNAs without affecting total protein or DNA methylation. Methylated RNA immunoprecipitation sequencing (MeRIP‐Seq) and RNA sequencing (RNA‐Seq) analyses further demonstrate that SHMT2‐Ser90 dephosphorylation accelerates the RNA degradation of oncogenic genes by reducing m6A modification, leading to the inhibition of tumorigenesis. Overall, this study elucidates a new regulatory mechanism of SHMT2 during oncogenesis and provides a theoretical basis for targeting SHMT2 as a therapeutic target in LUAD. MAPK1 phosphorylates SHMT2 at Ser90, and this phosphorylation enhances its protein stability, leading to increased SAM production and RNA m6A modification. This modification enhances the RNA stability of cancer‐promoting genes, thus promoting tumorigenesis. In contrast, PTPMT1 dephosphorylates SHMT2 at Ser90, followed by STUB1‐mediated ubiquitination and proteasomal degradation of SHMT2, resulting in the inhibition of tumorigenesis.