miR-449a targets HDAC-1 and induces growth arrest in prostate cancer.
Histone deacetylases (HDACs) are frequently overexpressed in broad range of cancer types, where they alter cellular epigenetic programming to promote cell proliferation and survival. However, the mechanism by which HDACs become overexpressed in human cancers remains somewhat of a mystery. In this study, we investigated the expression and functional significance of miR-449a in prostate cancer cells. Using real-time PCR, we found that miR-449a is downregulated in prostate cancer tissues relative to patient-matched control tissue. Introduction of miR-449a into PC-3 prostate cancer cells resulted in cell-cycle arrest, apoptosis and a senescent-like phenotype. In silico analysis of 3'-UTR regions identified a number of genes involved in cell-cycle regulation as putative targets of miR-449a. Using a luciferase 3'-UTR reporter system, we established that HDAC-1 (histone deacetylase 1), a gene that is frequently overexpressed in many types of cancer, is a direct target of miR-449a. Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells. Our findings provide new insight into the function of miRNA in regulating HDAC expression in normal versus cancerous tissue.
Noonan
E J
EJ
Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA. emily.noonan@gmail.com
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Pookot
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Basak
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Whitson
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Hirata
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Giardina
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Dahiya
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D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015971:Gene Expression Regulation, Enzymologic; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics
C436291:CDKN1B protein, human; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1