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Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer

Oncogene volume 32, pages 2891–2899 (2013)Cite this article

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Abstract

Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.

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Abbreviations

miRNA:

microRNA

ChIP:

chromatin immunoprecipitation

5-Aza-CdR:

5-Aza-2′-deoxycytidine

IP:

immunoprecipitation

FCS:

fetal calf serum

CSFCS:

charcoal-stripped fetal calf Serum

DHT:

dihydrotestosterone

PSA:

prostate specific antigen

AR:

androgen receptor

BRFS:

biochemical relapse free survival.

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Acknowledgements

We would like to thank Gillian Lehrbach, Ann-Maree Haynes, Ruth Pe Benito and Clarisse Puno for technical assistance. This work is supported by Cancer Institute NSW (CINSW), Cure Cancer Australia fellowships (TH), and National Health and Medical Research Council and CINSW project grants (SJC).

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Author notes

  1. Current address: Sydney Medical School, Edward Ford Building (A27), Fisher Road, The University of Sydney, New South Wales 2006, Australia.

Authors and Affiliations

  1. Epigenetics Group, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    T Hulf, T Sibbritt, E D Wiklund, K Patterson, J Z Song, C Stirzaker, W Qu, S Nair, L G Horvath, N J Armstrong, J G Kench, R L Sutherland & S J Clark

  2. Department of Molecular Biology, Aarhus University, Aarhus, Denmark

    E D Wiklund

  3. Department of Medical Oncology, Sydney Cancer Center, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

    L G Horvath

  4. School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia

    N J Armstrong

  5. Department of Tissue Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

    J G Kench

  6. St Vincent′s Clinical School, University of NSW, St Vincent′s Hospital, Darlinghurst, New South Wales, Australia

    S J Clark

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Correspondence to S J Clark.

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Hulf, T., Sibbritt, T., Wiklund, E. et al. Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer. Oncogene 32, 2891–2899 (2013). https://doi.org/10.1038/onc.2012.300

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