Abstract
Prostate cancer is the most commonly diagnosed non-cutaneous cancer and one of the leading causes of cancer death for North American men. Whereas localized prostate cancer can be cured, there is currently no cure for metastatic prostate cancer. Here we report a novel approach that utilizes designed chimeric transcription activator-like effectors (dTALEs) to control prostate cancer metastasis. Transfection of dTALEs of DNA methyltransferase or demethylase induced artificial, yet active locus-specific CpG and subsequent histone modifications. These manipulations markedly altered expression of endogenous CRMP4, a metastasis suppressor gene. Remarkably, locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 cells abolished metastasis, whereas locus-specific CpG methylation of the promoter in non-metastatic 22Rv1 cells induced metastasis. CRMP4-mediated metastasis suppression was found to require activation of Akt/Rac1 signaling and down-regulation of MMP-9 expression. This proof-of-concept study with dTALEs for locus-specific epigenomic manipulation validates the selected CpG methylation of CRMP4 gene as an independent biomarker for diagnosis and prognosis of prostate cancer metastasis and opens up a novel avenue for mechanistic research on cancer biology.
Highlights
Men with metastatic prostate cancer, are faced with poor prognosis, having median survival times in the range of only 3–7 years [1]
We demonstrate that designed chimeric transcript ion activator-like effectors (TALEs) containing a catalytic domain of DNA methyltransferase DNMT3A or DNA demethylase TET1 can turn prostate cancer metastasis on or off by altering CRMP4 expression through locusspecific modification of the gene promoter
We previously reported that CpG methylation in CRMP4 promoter Regions A and B (Supplementary Figure S1a) correlated with the metastatic status of prostate cancer [15]
Summary
Men with metastatic prostate cancer, are faced with poor prognosis, having median survival times in the range of only 3–7 years [1]. Sipuleucel-T [4], cabazitaxel [5], abiraterone (Zytiga) [6], and MDV3100 [7] have shown more prolonged overall survival benefit and have been approved by the FDA for treatment of the disease. None of these drugs are curative; they only marginally improve patients’ overall survival. There is a dire need for improved prognostic metastatic biomarkers to determine whether primary prostate cancers are potentially aggressive or indolent; in the latter case, patients can be spared from over treatment [9]
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