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BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy

Hiroshi Y Yamada1, Chinthalapally V Rao

  • 1Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), BRC1207, Oklahoma City, OK 73104, USA. hiroshi-yamada@ouhsc.edu

International Journal of Oncology
|September 30, 2009
PubMed

Insights

Bromodomain 8 (BRD8) protein is highly expressed in aggressive colorectal cancers, contributing to chemoresistance. Reducing BRD8 levels sensitizes cancer cells to chemotherapy, suggesting BRD8 as a therapeutic target for metastatic colorectal cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Metastatic colorectal cancer (mCRC) has a poor survival rate (<5%) largely due to chemoresistance.
  • Factors driving chemoresistance in colorectal cancers remain largely unknown, hindering therapeutic advancements.
  • Understanding these factors is crucial for improving treatment strategies and patient outcomes.

Purpose of the Study:

  • To identify key factors contributing to chemoresistance in aggressive colorectal cancers.
  • To investigate the role of human Bromodomain 8 (BRD8) in colorectal cancer progression and drug sensitivity.
  • To explore BRD8 as a potential therapeutic target for improving mCRC treatment outcomes.

Main Methods:

  • Expression cloning was utilized to identify influential factors in chemoresistance.
  • BRD8 protein expression levels were analyzed in various colorectal cancer cell lines and tissues.
  • Small interfering RNA (siRNA) was used to knockdown BRD8 expression.
  • Overexpression studies were conducted in HeLa cells to assess BRD8's effect on cell growth and drug resistance.

Main Results:

  • BRD8 protein expression is significantly elevated in metastatic colorectal cancer cell lines and aggressive tumor tissues compared to normal tissues.
  • siRNA-mediated knockdown of BRD8 induces cell death and growth delay in colorectal cancer cells.
  • BRD8 knockdown sensitizes surviving cells to spindle poisons and proteasome inhibitors (e.g., MG132).
  • Overexpression of BRD8 confers growth advantage and resistance to Taxol in HeLa cells.

Conclusions:

  • BRD8 plays a significant role in the survival and chemoresistance of aggressive colorectal cancers.
  • Elevated BRD8 expression is associated with tumor progression and advanced stages of colorectal cancer.
  • Targeting BRD8 presents a promising therapeutic strategy to enhance treatment efficacy for metastatic colorectal cancer.

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