title: Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer.
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.
authors.affiliation: Epigenetics Group, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Hulf
authors.forename: T
authors.initials: T
authors.lastname: Sibbritt
authors.forename: E D
authors.initials: ED
authors.lastname: Wiklund
authors.forename: K
authors.initials: K
authors.lastname: Patterson
authors.forename: J Z
authors.initials: JZ
authors.lastname: Song
authors.forename: C
authors.initials: C
authors.lastname: Stirzaker
authors.forename: W
authors.initials: W
authors.lastname: Qu
authors.forename: S
authors.initials: S
authors.lastname: Nair
authors.forename: L G
authors.initials: LG
authors.lastname: Horvath
authors.forename: N J
authors.initials: NJ
authors.lastname: Armstrong
authors.forename: J G
authors.initials: JG
authors.lastname: Kench
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: S J
authors.initials: SJ
authors.lastname: Clark
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D000368:Aged; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011499:Protein Processing, Post-Translational
chemical_list: D056913:Mediator Complex Subunit 1; D035683:MicroRNAs; C538855:MED1 protein, human; C534425:MIR205, human