Protein kinase Cδ negatively regulates hedgehog signaling by inhibition of Gli1 activity

Qingsong Cai, Jing Li, Tianyan Gao, Jingwu Xie, B. Mark Evers

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Constitutive activation of the hedgehog pathway is implicated in the development of many human malignancies; hedgehog targets, PTCH1 and Gli1, are markers of hedgehog signaling activation and are expressed in most hedgehog-associated tumors. Protein kinase Cδ (PKCδ) generally slows proliferation and induces cell cycle arrest of various cell lines. In this study, we show that activated PKCδ (wild-type PKCδ stimulated by phorbol 12-myristate 13-acetate or constitutively active PKCδ) decreased Gli-luciferase reporter activity in NIH/3T3 cells, as well as the endogenous hedgehog-responsive gene PTCH1. In human hepatoma (i.e. Hep3B) cells, wild-type PKCδ and constitutively active PKCδ decreased the expression levels of endogenous Gli1 and PTCH1. In contrast, PKCδ siRNA increased the expression levels of these target genes. Silencing of PKCδ by siRNA rescued the inhibition of cell growth by KAAD-cyclopamine, an antagonist of hedgehog signaling element Smoothened, suggesting that PKCδ acts downstream of Smoothened. The biological relevance of our study is shown in hepatocellular carcinoma where we found that hepatocellular carcinoma with detectable hedgehog signaling had weak or no detectable expression of PKCδ, whereas PKCδ highly expressing tumors had no detectable hedgehog signaling. Our results demonstrate that PKCδ alters hedgehog signaling by inhibition of Gli protein transcriptional activity. Furthermore, our findings suggest that, in certain cancers, PKCδ plays a role as a negative regulator of tumorigenesis by regulating hedgehog signaling.

Original languageEnglish (US)
Pages (from-to)2150-2158
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number4
DOIs
StatePublished - Jan 23 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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