title: miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways.
abstract: OBJECTIVE
  miRNAs can act as oncomirs or tumor-suppressor miRs in cancer. This study was undertaken to investigate the status and role of miR-34b in prostate cancer.
  
  
  METHODS
  Profiling of miR-34b was carried out in human prostate cancer cell lines and clinical samples by quantitative real-time PCR and in situ hybridization. Statistical analyses were done to assess diagnostic/prognostic potential. Biological significance was elucidated by carrying out a series of experiments in vitro and in vivo.
  
  
  RESULTS
  We report that miR-34b is silenced in human prostate cancer and the mechanism is through CpG hypermethylation. miR-34b directly targeted methyltransferases and deacetylases resulting in a positive feedback loop inducing partial demethylation and active chromatin modifications. miR-34b expression could predict overall and recurrence-free survival such that patients with high miR-34b levels had longer survival. Functionally, miR-34b inhibited cell proliferation, colony formation, migration/invasion, and triggered G(0)/G(1) cell-cycle arrest and apoptosis by directly targeting the Akt and its downstream proliferative genes. miR-34b caused a decline in the mesenchymal markers vimentin, ZO1, N-cadherin, and Snail with an increase in E-cadherin expression, thus inhibiting epithelial-to-mesenchymal transition. Finally we showed the antitumor effect of miR-34b in vivo. MiR-34b caused a dramatic decrease in tumor growth in nude mice compared with cont-miR.
  
  
  CONCLUSIONS
  These findings offer new insight into the role of miR-34b in the inhibition of prostate cancer through demethylation, active chromatin modification, and Akt pathways and may provide a rationale for the development of new strategies targeting epigenetic regulation of miRNAs for the treatment of prostate cancer.
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA 94121, USA.
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.forename: Mohd Saif
authors.initials: MS
authors.lastname: Zaman
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020121:5' Untranslated Regions; D002843:Chromatin; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D004248:DNA (Cytosine-5-)-Methyltransferases; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases