Regulation of expression of deoxyhypusine hydroxylase (DOHH), the enzyme that catalyzes the activation of eIF5A, by miR-331-3p and miR-642-5p in prostate cancer cells.
The enzyme deoxyhypusine hydroxylase (DOHH) catalyzes the activation of eukaryotic translation initiation factor (eIF5A), a protein essential for cell growth. Using bioinformatic predictions and reporter gene assays, we have identified a 182-nt element within the DOHH 3'-untranslated region (3'-UTR) that contains a number of target sites for miR-331-3p and miR-642-5p. Quantitative RT-PCR studies demonstrated overexpression of DOHH mRNA and underexpression of miR-331-3p and miR-642-5p in several prostate cancer cell lines compared with normal prostate epithelial cells. Transient overexpression of miR-331-3p and/or miR-642-5p in DU145 prostate cancer cells reduced DOHH mRNA and protein expression and inhibited cell proliferation. We observed synergistic growth inhibition with the combination of miR-331-3p and miR-642-5p and mimosine, a pharmacological DOHH inhibitor. Finally, we identified a significant inverse relationship between the expression of miR-331-3p or miR-642-5p and DOHH in a cohort of human prostate cancer tissues. Our results suggest a novel role for miR-331-3p and miR-642-5p in the control of prostate cancer cell growth via the regulation of DOHH expression and eIF5A activity.
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia.
Michael R
MR
Epis
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia.
Keith M
KM
Giles
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia.
Felicity C
FC
Kalinowski
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia.
Andrew
A
Barker
Uropath Pty, Ltd., West Leederville, Western Australia 6007, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia 6009, Australia.
Ronald J
RJ
Cohen
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia; School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia 6009, Australia. Electronic address: peter.leedman@uwa.edu.au.
Peter J
PJ
Leedman
D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000097574:Eukaryotic Translation Initiation Factor 5A
D020413:3' Untranslated Regions; D035683:MicroRNAs; D006899:Mixed Function Oxygenases; D009363:Neoplasm Proteins; D010448:Peptide Initiation Factors; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C544460:MIRN331 microRNA, human; C571933:MIRN642 microRNA, human; C047991:deoxyhypusine hydroxylase