Protein kinase Cdelta negatively regulates hedgehog signaling by inhibition of Gli1 activity.
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 Cdelta (PKCdelta) generally slows proliferation and induces cell cycle arrest of various cell lines. In this study, we show that activated PKCdelta (wild-type PKCdelta stimulated by phorbol 12-myristate 13-acetate or constitutively active PKCdelta) 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 PKCdelta and constitutively active PKCdelta decreased the expression levels of endogenous Gli1 and PTCH1. In contrast, PKCdelta siRNA increased the expression levels of these target genes. Silencing of PKCdelta by siRNA rescued the inhibition of cell growth by KAAD-cyclopamine, an antagonist of hedgehog signaling element Smoothened, suggesting that PKCdelta 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 PKCdelta, whereas PKCdelta highly expressing tumors had no detectable hedgehog signaling. Our results demonstrate that PKCdelta alters hedgehog signaling by inhibition of Gli protein transcriptional activity. Furthermore, our findings suggest that, in certain cancers, PKCdelta plays a role as a negative regulator of tumorigenesis by regulating hedgehog signaling.
Cai
Qingsong
Q
Department of Surgery, Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, TX 77555-0536, USA.
Li
Jing
J
Gao
Tianyan
T
Xie
Jingwu
J
Evers
B Mark
BM
D021581:Active Transport, Cell Nucleus; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051745:Protein Kinase C-delta