Beta-catenin represses protein kinase D1 gene expression by non-canonical pathway through MYC/MAX transcription complex in prostate cancer
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Bita Nickkholgh1,2, Sivanandane Sittadjody2, Michael B. Rothberg3, Xiaolan Fang2,8,9, Kunzhao Li4, Jeff W. Chou5, Gregory A. Hawkins6 and K.C. Balaji2,3,7,8
1Department of Physiology-Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
2Wake Forest Institute for Regenerative Medicine (WFRM), Wake Forest University School of Medicine, Winston-Salem, NC, USA
3Department of Urology, Wake Forest Baptist Health, Winston Salem, NC, USA
4Biology Department, Wake Forest University, Winston-Salem, NC, USA
5Department of Biostatistical Sciences, Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA
6Center for Genomics and Personalized Medicine and WFB Comprehensive Cancer Center, Winston-Salem, NC, USA
7W.G.(Bill) Hefner Veterans Administration Medical Center, Salisbury, NC, USA
8Department of Cancer Biology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA
9Current/Present address: Clinical Bioinformatics, New York Genome Center, New York, NY, USA
K. C. Balaji, email: [email protected]
Keywords: prostate cancer, protein kinase D1, beta-catenin, MYC, MAX
Received: June 01, 2017 Accepted: July 09, 2017 Published: August 12, 2017
Down regulation of Protein Kinase D1 (PrKD1), a novel serine threonine kinase, in prostate, gastric, breast and colon cancers in humans leads to disease progression. While the down regulation of PrKD1 by DNA methylation in gastric cancer and by nuclear beta-catenin in colon cancer has been shown, the regulatory mechanisms in other cancers are unknown. Because we had demonstrated that PrKD1 is the only known kinase to phosphorylate threonine 120 (T120) of beta-catenin in prostate cancer resulting in increased nuclear beta-catenin, we explored the role of beta-catenin in gene regulation of PrKD1. An initial CHIP assay identified potential binding sites for beta-catenin in and downstream of PrKD1 promoter and sequencing confirmed recruitment of beta-catenin to a 166 base pairs sequence upstream of exon 2. Co-transfection studies with PrKD1-promoter-reporter suggested that beta-catenin represses PrKD1 promoter. Efforts to identify transcription factors that mediate the co-repressor effects of beta-catenin identified recruitment of both MYC and its obligate heterodimer MAX to the same binding site as beta-catenin on the PrKD1 promoter site. Moreover, treatment with MYC inhibitor rescued the co-repressor effect of beta-catenin on PrKD1 gene expression. Prostate specific knock out of PrKD1 in transgenic mice demonstrated increased nuclear expression of beta-catenin validating the in vitro studies. Functional studies showed that nuclear translocation of beta-catenin as a consequence of PrKD1 down regulation, increases AR transcriptional activity with attendant downstream effects on androgen responsive genes. In silico human gene expression analysis confirmed the down regulation of PrKD1 in metastatic prostate cancer correlated inversely with the expression of MAX, but not MYC, and positively with MXD1, a competing heterodimer of MAX, suggesting that the dimerization of MAX with either MYC or MXD1 regulates PrKD1 gene expression. The study has identified a novel auto-repressive loop that perpetuates PrKD1 down regulation through beta-catenin/MYC/MAX protein complex.
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