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Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma

Koji Ueno1, Hiroshi Hirata, Shahana Majid

  • 1Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA.

Molecular Carcinogenesis
|January 27, 2011
PubMed

Insights

Dickkopf-3 (Dkk-3) gene inactivation in renal cell carcinoma (RCC) is regulated by histone modification. Dkk-3 inhibits renal cancer growth by promoting apoptosis and cell cycle arrest, independent of the Wnt/beta-catenin pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Wnt signaling pathway activation is common in cancers.
  • Wnt antagonist genes, like Dkk-3, are often inactivated in tumors.
  • Mechanisms of Dkk-3 inactivation in renal cell carcinoma (RCC) remain unclear.

Purpose of the Study:

  • Investigate epigenetic mechanisms regulating Dkk-3 expression in RCC.
  • Determine the functional impact of Dkk-3 on RCC cell growth and apoptosis.
  • Elucidate the signaling pathways involved in Dkk-3-mediated effects.

Main Methods:

  • Analysis of Dkk-3 expression in RCC cells.
  • Assessment of CpG island DNA methylation and histone modification.
  • Transfection of RCC cell lines with Dkk-3 expression plasmid.
  • Evaluation of cell proliferation, apoptosis, and cell cycle progression.
  • In vivo tumor growth studies in nude mice.

Main Results:

  • Dkk-3 expression is regulated by histone modification, not DNA methylation, in RCC.
  • Dkk-3 transfection inhibited renal cancer cell proliferation and promoted apoptosis.
  • Dkk-3 induced apoptosis via the noncanonical JNK pathway, not Wnt/beta-catenin.
  • Dkk-3 overexpression led to G(0)/G(1) arrest and increased p21 expression.
  • Tumor growth was reduced in vivo in Dkk-3-expressing cells.

Conclusions:

  • Dkk-3 mRNA expression in renal cancer is epigenetically regulated by histone modification.
  • Dkk-3 acts as a tumor suppressor in RCC by modulating cell cycle and apoptosis.
  • Dkk-3 inhibits renal cancer progression through noncanonical JNK and cell cycle pathways.

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