title: Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression.
abstract: Androgen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker.
authors.affiliation: DepartmentS of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Lin
authors.forename: Ya-Lin
authors.initials: YL
authors.lastname: Chiu
authors.forename: Samprit
authors.initials: S
authors.lastname: Banerjee
authors.forename: Kyung
authors.initials: K
authors.lastname: Park
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.forename: Eugenia
authors.initials: E
authors.lastname: Giannopoulou
authors.forename: Pedro
authors.initials: P
authors.lastname: Alves
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Tewari
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000502:physiology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2