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miRNA-34b Inhibits Prostate Cancer through Demethylation, Active Chromatin Modifications, and AKT Pathways

Authors
 Shahana Majid  ;  Altaf A. Dar  ;  Sharanjot Saini  ;  Varahram Shahryari  ;  Sumit Arora  ;  Mohd Saif Zaman  ;  Inik Chang  ;  Soichiro Yamamura  ;  Yuichiro Tanaka  ;  Takeshi Chiyomaru  ;  Guoren Deng  ;  Rajvir Dahiya 
Citation
 Clinical Cancer Research, Vol.19(1) : 73-84, 2013 
Journal Title
 Clinical Cancer Research 
ISSN
 1078-0432 
Issue Date
2013
MeSH
5' Untranslated Regions ; Animals ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Chromatin/genetics* ; Chromatin/metabolism* ; CpG Islands ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; Epigenesis, Genetic ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; Male ; Mice ; MicroRNAs/genetics* ; MicroRNAs/metabolism ; Neoplasm Invasiveness/genetics ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms/metabolism* ; Prostatic Neoplasms/mortality ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins c-akt/metabolism* ; Signal Transduction*
Keywords
5' Untranslated Regions ; Animals ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Chromatin/genetics* ; Chromatin/metabolism* ; CpG Islands ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; Epigenesis, Genetic ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; Male ; Mice ; MicroRNAs/genetics* ; MicroRNAs/metabolism ; Neoplasm Invasiveness/genetics ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms/metabolism* ; Prostatic Neoplasms/mortality ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins c-akt/metabolism* ; Signal Transduction*
Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. CONCLUSION: 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.
Files in This Item:
T201303674.pdf Download
DOI
10.1158/1078-0432.CCR-12-2952
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88283
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