Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression

Zhongyuan Gao1, Ting Yuan2, Xiao Zhou2

  • 1a Department of Pharmacology , Nanjing Medical University , Nanjing , Jiangsu Province , China.

Cancer Biology & Therapy
|January 16, 2018
PubMed

Insights

Bromodomain and extraterminal domain (BET) inhibitors suppress non-small cell lung cancer growth by downregulating eIF4E transcription. Targeting both BET proteins and eIF4E offers a novel therapeutic strategy for lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Lung cancer is a leading cause of cancer death globally.
  • Bromodomain and extraterminal domain (BET) proteins regulate gene transcription, but their role in non-small cell lung carcinoma (NSCLC) is unclear.
  • eIF4E is crucial for gene translation and lung cancer progression.

Purpose of the Study:

  • To investigate the mechanism of BET protein involvement in NSCLC.
  • To explore the relationship between BET proteins and eIF4E in NSCLC.
  • To evaluate BET inhibitors as a potential therapeutic strategy for NSCLC.

Main Methods:

  • Utilized BET inhibitors (JQ1, I-BET151) and BRD4 siRNA in NSCLC cell lines.
  • Assessed cell growth, eIF4E expression (mRNA and protein), and promoter activity.
  • Performed luciferase reporter assays and xenograft mouse models.

Main Results:

  • BET inhibitors and BRD4 knockdown suppressed NSCLC growth and reduced eIF4E levels.
  • Overexpression of eIF4E partially reversed JQ1's inhibitory effect, while knockdown enhanced it.
  • JQ1 and BRD4 knockdown decreased eIF4E mRNA levels and inhibited its promoter activity, with reduced BRD4 binding.

Conclusions:

  • BET inhibition suppresses NSCLC growth by decreasing eIF4E transcription and expression.
  • This study reveals a novel mechanism of BET-regulated eIF4E in lung cancer.
  • Co-targeting eIF4E presents a promising strategy to enhance BET-targeted cancer therapy.

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