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CDK5RAP3 is a novel repressor of p14ARF in hepatocellular carcinoma cells

Grace Wing-Yan Mak1, Wai-Lung Lai, Yuan Zhou

  • 1Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Plos One
|August 4, 2012
PubMed

Insights

CDK5 regulatory subunit associated protein 3 (CDK5RAP3) promotes liver cancer metastasis by downregulating the p14(ARF) tumor suppressor. This study reveals a new mechanism involving CDK5RAP3 binding to the p14(ARF) promoter.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hepatology

Background:

  • CDK5RAP3 (CDK5 regulatory subunit associated protein 3) is implicated in hepatocarcinogenesis and metastasis.
  • The precise mechanisms by which CDK5RAP3 promotes hepatocellular carcinoma (HCC) metastasis are not fully understood.

Purpose of the Study:

  • To investigate the role of CDK5RAP3 in HCC metastasis beyond its known activation of PAK4.
  • To elucidate the regulatory relationship between CDK5RAP3 and the p14(ARF) tumor suppressor in HCC.

Main Methods:

  • Stable knockdown of CDK5RAP3 in SMMC-7721 HCC cells.
  • Analysis of p14(ARF) mRNA and protein expression.
  • Chromatin immunoprecipitation (ChIP) assay to assess CDK5RAP3 binding to the p14(ARF) promoter.
  • Rescue experiments involving p14(ARF) knockdown in CDK5RAP3-depleted cells.

Main Results:

  • CDK5RAP3 knockdown led to increased p14(ARF) expression at both mRNA and protein levels.
  • Ectopic expression of CDK5RAP3 suppressed p14(ARF) transcription.
  • CDK5RAP3 was shown to bind directly to the p14(ARF) promoter in vivo.
  • Knockdown of p14(ARF) abrogated the anti-invasive effects observed after CDK5RAP3 knockdown.

Conclusions:

  • CDK5RAP3 promotes HCC metastasis through the transcriptional downregulation of the p14(ARF) tumor suppressor.
  • This study identifies a novel mechanism of HCC metastasis regulation by CDK5RAP3 via p14(ARF).

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