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BRD4 inhibitor IBET upregulates p27kip/cip protein stability in neuroendocrine tumor cells

Lei Wang1,2, Smita Matkar2, Gengchen Xie3

  • 1a Department of Urology , Renmin Hospital of Wuhan University , Wuhan , P.R. China.

Cancer Biology & Therapy
|March 11, 2017
PubMed

Insights

A new epigenetic drug inhibitor (IBET) effectively targets neuroendocrine tumor (NET) cells resistant to standard therapies. This compound increases the stability of a key cell cycle inhibitor, p27, halting NET cell proliferation.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Neuroendocrine tumors (NETs) are increasing in prevalence.
  • Current therapies like Octreotide, Capecitabine, and Temozolimide show limited efficacy against progressing and metastasizing NETs.
  • There is a critical need for novel therapeutic strategies for NET treatment.

Purpose of the Study:

  • To investigate the efficacy of an inhibitor targeting the epigenetic regulator Brd4 (IBET) against drug-resistant neuroendocrine tumor cells.
  • To elucidate the molecular mechanisms underlying IBET's anti-tumor effects in NETs.

Main Methods:

  • Utilized human neuroendocrine tumor BON cells.
  • Assessed the effects of IBET on cell proliferation and drug resistance.
  • Analyzed protein and mRNA levels of key cell cycle regulators, including p27 and Skp2.
  • Investigated the role of protein stability and ubiquitinylation in IBET's mechanism of action.

Main Results:

  • BON cells exhibited resistance to Octreotide, Capecitabine, and Temozolimide.
  • IBET potently inhibited NET cell proliferation.
  • IBET increased protein levels of the cyclin-dependent kinase inhibitor p27, without affecting its mRNA.
  • IBET enhanced p27 protein stability by suppressing Skp2, an E3 ligase responsible for p27 degradation.

Conclusions:

  • IBET represents a promising therapeutic agent for neuroendocrine tumors, particularly those resistant to conventional treatments.
  • The mechanism involves Brd4 inhibition, leading to increased p27 protein stability and subsequent repression of NET cell proliferation.
  • This study uncovers a novel therapeutic pathway for managing neuroendocrine tumors.
Keywords:
Brd4IBETSkp2neuroendocrine tumorp27

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