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BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis

Xingchen Dong1, Xiangming Hu1, Jinjing Chen1

  • 1Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.

Cell Death & Disease
|February 14, 2018
PubMed

Insights

BET inhibitor JQ1 halts gastric cancer growth by triggering cellular senescence. This occurs via the E2F/miR-106b-5p/p21 pathway, revealing a novel therapeutic mechanism for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Bromodomain and Extra-Terminal (BET) proteins are epigenetic regulators implicated in cancer.
  • BET inhibitors show anti-tumor potential, but their precise anti-proliferative mechanisms require further elucidation.
  • Gastric cancer remains a significant health concern with a need for novel therapeutic strategies.

Purpose of the Study:

  • To investigate the mechanism by which BET inhibitor JQ1 suppresses gastric cancer cell proliferation.
  • To identify the specific BET protein and molecular pathways involved in JQ1-induced anti-cancer effects.
  • To explore the role of cellular senescence in the anti-proliferative activity of BET inhibitors in gastric cancer.

Main Methods:

  • Gastric cancer cell lines were treated with BET inhibitor JQ1.
  • BRD4 expression was modulated using genetic depletion techniques.
  • Cellular senescence was assessed via SA-β-Gal staining and p21 expression analysis.
  • MicroRNA (miR-106b-5p) levels and their interaction with p21 mRNA were investigated.
  • Chromatin immunoprecipitation and E2F inhibition were employed to study transcriptional regulation.

Main Results:

  • JQ1 treatment induced cellular senescence and suppressed proliferation and invasiveness in gastric cancer cells.
  • Depletion of BRD4, but not other BET proteins, mimicked JQ1's senescence-inducing effects.
  • BRD4 regulated p21 levels post-transcriptionally through miR-106b-5p, which targets p21 mRNA.
  • E2F inhibition disrupted BRD4 binding to the miR-106b-5p promoter, decreasing its transcription and increasing p21 levels and senescence.

Conclusions:

  • BRD4 plays a critical role in regulating gastric cancer cell proliferation through the induction of cellular senescence.
  • A novel regulatory axis involving E2F, BRD4, miR-106b-5p, and p21 mediates JQ1's anti-cancer effects.
  • These findings offer new insights into BET inhibitor mechanisms and potential therapeutic applications in gastric cancer.

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