MicroRNA profiling of novel African American and Caucasian Prostate Cancer cell lines reveals a reciprocal regulatory relationship of miR-152 and DNA methyltranferase 1

Shaniece C. Theodore, Melissa B Davis, Fu Zhao, Honghe Wang, Dongquan Chen, Johng Rhim, Windy Dean-Colomb, Timothy Turner, Weidong Ji, Guohua Zeng, William Grizzle, Clayton Yates

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3512-3525
Number of pages14
JournalOncotarget
Volume5
Issue number11
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

MicroRNAs
African Americans
Prostatic Neoplasms
Cell Line
DNA
decitabine
Informatics
3' Untranslated Regions
Tumor Cell Line
Epigenomics
Small Interfering RNA
Neoplasm Metastasis
Recurrence
Survival
Growth
Neoplasms
Ectopic Gene Expression
Therapeutics

Keywords

  • African American
  • DNA methylation
  • Prostate cancer
  • miRNA

ASJC Scopus subject areas

  • Oncology

Cite this

MicroRNA profiling of novel African American and Caucasian Prostate Cancer cell lines reveals a reciprocal regulatory relationship of miR-152 and DNA methyltranferase 1. / Theodore, Shaniece C.; Davis, Melissa B; Zhao, Fu; Wang, Honghe; Chen, Dongquan; Rhim, Johng; Dean-Colomb, Windy; Turner, Timothy; Ji, Weidong; Zeng, Guohua; Grizzle, William; Yates, Clayton.

In: Oncotarget, Vol. 5, No. 11, 01.01.2014, p. 3512-3525.

Research output: Contribution to journalArticle

Theodore, SC, Davis, MB, Zhao, F, Wang, H, Chen, D, Rhim, J, Dean-Colomb, W, Turner, T, Ji, W, Zeng, G, Grizzle, W & Yates, C 2014, 'MicroRNA profiling of novel African American and Caucasian Prostate Cancer cell lines reveals a reciprocal regulatory relationship of miR-152 and DNA methyltranferase 1', Oncotarget, vol. 5, no. 11, pp. 3512-3525. https://doi.org/10.18632/oncotarget.1953
Theodore, Shaniece C. ; Davis, Melissa B ; Zhao, Fu ; Wang, Honghe ; Chen, Dongquan ; Rhim, Johng ; Dean-Colomb, Windy ; Turner, Timothy ; Ji, Weidong ; Zeng, Guohua ; Grizzle, William ; Yates, Clayton. / MicroRNA profiling of novel African American and Caucasian Prostate Cancer cell lines reveals a reciprocal regulatory relationship of miR-152 and DNA methyltranferase 1. In: Oncotarget. 2014 ; Vol. 5, No. 11. pp. 3512-3525.
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abstract = "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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