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CARM1-mediated OGT arginine methylation promotes non-small cell lung cancer glycolysis by stabilizing OGT

Luyao Lin1, Qingxia Yuan2, Jiayi Gu2

  • 1The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, 130024, Changchun, China.

Cell Death & Disease
|December 23, 2024
PubMed

Insights

Coactivator associated arginine methyltransferase 1 (CARM1) stabilizes O-GlcNAc transferase (OGT) via arginine methylation, promoting tumor glycolysis and non-small cell lung cancer (NSCLC) cell proliferation. This CARM1-USP9X-OGT axis offers a potential therapeutic target for NSCLC.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • O-GlcNAcylation, regulated by O-GlcNAc transferase (OGT), is crucial for tumor glycolysis.
  • The precise regulatory mechanisms of OGT, particularly in response to metabolic cues, remain incompletely understood in non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To elucidate the mechanism by which OGT is regulated in NSCLC cells.
  • To investigate the role of coactivator associated arginine methyltransferase 1 (CARM1) in sensing glucose levels and modulating OGT activity.
  • To identify potential therapeutic targets within the identified regulatory axis for NSCLC treatment.

Main Methods:

  • Investigated the sensing of extracellular glucose levels by CARM1 in NSCLC cells.
  • Utilized arginine methylation assays to determine OGT modification by CARM1.
  • Examined the interaction between CARM1, OGT, and the deubiquitinase USP9X.
  • Assessed the impact of OGT arginine methylation on global O-GlcNAcylation, glycolysis, c-Myc expression, and NSCLC cell proliferation in vitro and in vivo.
  • Correlated OGT and CARM1 expression in human NSCLC samples.

Main Results:

  • Increased extracellular glucose upregulated both CARM1 and OGT expression in NSCLC cells.
  • CARM1 was found to methylate OGT at arginine 348, enhancing OGT stability through USP9X binding.
  • This arginine methylation of OGT led to increased global O-GlcNAcylation and promoted NSCLC glycolysis.
  • OGT arginine methylation also upregulated c-Myc expression, driving NSCLC cell proliferation in vitro and in vivo.
  • A positive correlation between OGT and CARM1 expression was observed in human NSCLC samples.

Conclusions:

  • CARM1 acts as a glucose sensor, stabilizing OGT through arginine methylation in response to elevated glucose levels.
  • The CARM1-USP9X-OGT axis plays a significant role in promoting glycolysis and proliferation in NSCLC.
  • This regulatory axis represents a promising novel therapeutic strategy for NSCLC treatment.

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