MicroRNA profiling of novel African American and Caucasian Prostate Cancer cell lines reveals a reciprocal regulatory relationship of miR-152 and DNA methyltranferase 1
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Shaniece C. Theodore1, Melissa Davis 3, Fu Zhao1 , Honghe Wang1, Dongquan Chen6, Johng Rhim2 , Windy Dean-Colomb7, Timothy Turner1, Weidong Ji 5, Guohua Zeng 5, William Grizzle4, Clayton Yates1
1 Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL
2 Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD
3 Department of Genetics, University of Georgia, Athens, GA
4 Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, AL
5 Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical College, Guangdong Provincial Key Laboratory of Urology, 1 Kangda Road, Guangzhou 510230, China
6 Division of Preventive Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL
7 Department of Oncologic Sciences, University of South Alabama Mitchell Cancer Institute, Mobile, AL
Clayton Yates, email:
Keywords: miRNA, DNA methylation, African American, prostate cancer
Received: April 9, 2014 Accepted: May 7, 2014 Published: May 8, 2014
miRNA expression in African American compared to Caucasian PCa patients has not been widely explored. Herein, we probed the miRNA expression profile of novel AA and CA derived prostate cancer cell lines. We found a unique miRNA signature associated with AA cell lines, independent of tumor status. Evaluation of the most differentially expressed miRNAs showed that miR-132, miR-367b, miR-410, and miR-152 were decreased in more aggressive cells, and this was reversed after treatment of the cells with 5-aza-2′-deoxycytidine. Sequencing of the miR-152 promoter confirmed that it was highly methylated. Ectopic expression of miR-152 resulted in decreased growth, migration, and invasion. Informatics analysis of a large patient cohort showed that decreased miR-152 expression correlated with increased metastasis and a decrease in biochemical recurrence free survival. Analysis of 39 prostate cancer tissues with matched controls (20 AA and 19 CA), showed that 50% of AA patients had statistically significant lower miR-152 expression compared to only 35% of CA patients. Ectopic expression of miR-152 in LNCaP, PC-3, and MDA-PCa-2b cells down-regulated DNA (cytosine-5)-methyltransferase 1 (DNMT1) through direct binding in the DNMT1 3’UTR. There appeared to be a reciprocal regulatory relationship of miR-152/DNMT1 expression, as cells treated with siRNA DNMT1 caused miR-152 to be re-expressed in all cell lines. In summary, these results demonstrate that epigenetic regulation of miR-152/DNMT1 may play an important role in multiple events that contribute to the aggressiveness of PCa tumors, with an emphasis on AA PCa patients .
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