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RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting

Lei Chen1, Wenjing Zhang1, Dan Chen2

  • 1Institute of Cancer Stem Cells and the Second Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, 116044, China.

Signal Transduction and Targeted Therapy
|April 20, 2023
PubMed

Insights

RNA-binding protein 4 (RBM4) promotes esophageal squamous cell carcinoma (ESCC) progression by inhibiting LKB1-mediated senescence. Targeting RBM4 or LKB1 may offer new therapeutic strategies for ESCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cellular senescence acts as a tumor suppressor mechanism.
  • Mechanisms by which cancer cells evade senescence are not fully understood.
  • Esophageal squamous cell carcinoma (ESCC) progression involves complex molecular alterations.

Purpose of the Study:

  • To elucidate the role of RNA-binding protein 4 (RBM4) in ESCC.
  • To investigate how RBM4 influences cellular senescence and cancer metabolism.
  • To identify potential therapeutic targets for ESCC.

Main Methods:

  • Analysis of RBM4 expression in ESCC tissues.
  • Investigating the effect of RBM4 modulation on senescence induction (H-RAS, doxorubicin).
  • Studying the interaction between RBM4, LKB1, and downstream signaling pathways (AMPK, mTOR).
  • Assessing the impact of RBM4/LKB1 levels on patient survival and drug sensitivity.

Main Results:

  • RBM4 is upregulated in ESCC and promotes malignant phenotype.
  • RBM4 overexpression inhibits senescence by disrupting the LKB1/STRAD/MO25 complex, leading to LKB1 degradation.
  • RBM4 depletion induces senescence via the LKB1-AMPK-mTOR pathway.
  • High RBM4/low LKB1 expression correlates with poor prognosis in ESCC patients.
  • ESCC cells with high RBM4/low LKB1 are sensitive to glutaminase inhibitor CB-839.

Conclusions:

  • RBM4 promotes ESCC by inhibiting senescence through LKB1 destabilization and enhancing glutamine metabolism.
  • RBM4/LKB1 expression levels can serve as prognostic biomarkers for ESCC.
  • Targeting RBM4 or utilizing glutaminase inhibitors like CB-839 shows therapeutic potential for ESCC.

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