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CHD4 promotes acquired chemoresistance and tumor progression by activating the MEK/ERK axis

Jing Wu1, Zhijun Zhou2, Jin Li2

  • 1Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, China.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|January 5, 2023
PubMed
Abstract

Insights

Chromodomain helicase DNA-binding protein 4 (CHD4) drives chemoresistance in gastric cancer by increasing drug efflux and activating the MEK/ERK pathway. Targeting CHD4 offers a promising strategy to overcome treatment resistance in GC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Chemoresistance is a significant obstacle in gastric cancer (GC) treatment.
  • The role of Chromodomain helicase DNA-binding protein 4 (CHD4) in GC chemoresistance is currently unknown.
  • CHD4 is involved in chromatin remodeling and has critical roles in various cancers.

Purpose of the Study:

  • To investigate the role of CHD4 in gastric cancer chemoresistance.
  • To elucidate the underlying mechanisms by which CHD4 influences chemoresistance.
  • To identify CHD4 as a potential therapeutic target for overcoming GC chemoresistance.

Main Methods:

  • Examined CHD4 expression using immunohistochemistry and Western blotting.
  • Assessed CHD4's impact on GC cell proliferation and chemoresistance in vitro and in vivo.
  • Identified CHD4-binding proteins via immunoprecipitation and liquid chromatography-mass spectrometry.
  • Explored protein-protein interactions using proximity ligation assays.

Main Results:

  • CHD4 expression is upregulated in GC tissues and associated with chemoresistance.
  • Overexpression of CHD4 enhances GC cell proliferation and chemoresistance.
  • CHD4 knockdown induces apoptosis, cell cycle arrest, and increases sensitivity to cisplatin by reducing drug efflux.
  • CHD4 promotes MEK/ERK pathway activation through interaction with ERK1/2 and MEK1/2.
  • CHD4 knockdown suppressed tumor growth in a mouse xenograft model.

Conclusions:

  • CHD4 plays a critical role in mediating chemoresistance in gastric cancer.
  • CHD4-induced multi-drug efflux is a key mechanism of chemoresistance.
  • Targeting CHD4 presents a promising therapeutic strategy to overcome acquired chemoresistance in GC.
Keywords:
CHD4ChemoresistanceERK1/2

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