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Phosphorylated SHMT2 Regulates Oncogenesis Through m6A Modification in Lung Adenocarcinoma

Tianyu Han1,2,3, Yanan Wang1,2,3, Minzhang Cheng1,2,3

  • 1Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi, 330006, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 9, 2024
PubMed

Insights

Targeting serine hydroxymethyltransferase 2 (SHMT2) is a new strategy for lung adenocarcinoma (LUAD). Upregulation of SHMT2, driven by MAPK1, promotes LUAD. Inhibiting SHMT2 reduces tumor growth by lowering RNA methylation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Targeting cancer metabolism is a key therapeutic strategy.
  • Lung adenocarcinoma (LUAD) exhibits specific metabolic vulnerabilities.
  • Serine hydroxymethyltransferase 1/2 (SHMT1/2) are potential metabolic targets in LUAD.

Purpose of the Study:

  • To screen for metabolic targets in LUAD using a compound library.
  • To elucidate the regulatory mechanism of SHMT2 in LUAD.
  • To investigate the therapeutic potential of targeting SHMT2 in LUAD.

Main Methods:

  • Compound library screening for metabolic enzyme inhibitors.
  • Investigating SHMT2 upregulation mechanism via MAPK1-mediated phosphorylation.
  • Assessing the impact of SHMT2-Ser90 dephosphorylation on S-adenosylmethionine and m6A levels.
  • Utilizing MeRIP-Seq and RNA-Seq to analyze RNA modification and degradation.

Main Results:

  • SHIN1, an SHMT1/2 inhibitor, specifically inhibits LUAD cells, dependent on SHMT2 overexpression.
  • MAPK1-mediated phosphorylation at Ser90 stabilizes SHMT2 by inhibiting STUB1-mediated degradation.
  • SHMT2-Ser90 dephosphorylation reduces S-adenosylmethionine and global RNA m6A levels.
  • SHMT2 inhibition accelerates oncogenic gene RNA degradation, inhibiting tumorigenesis.

Conclusions:

  • A novel regulatory mechanism for SHMT2 in LUAD oncogenesis is identified.
  • MAPK1-mediated phosphorylation of SHMT2 is crucial for LUAD progression.
  • Targeting SHMT2 represents a promising therapeutic strategy for LUAD.
Keywords:
N6‐methyladenosineSHMT2lung adenocarcinomaphosphorylationubiquitination

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