The Landscape of microRNA Targeting in Prostate Cancer Defined by AGO-PAR-CLIP.
MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable ribonucleoside-enhanced cross-linking immunoprecipitation of the Argonaute protein in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of PCa and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that androgen receptor is the most frequently targeted PCa oncogene and that miR-148a targets the largest number of known PCa drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that, even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in PCa and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA.
Mark P
MP
Hamilton
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Kimal I
KI
Rajapakshe
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA.
David A
DA
Bader
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA.
Jasmina Z
JZ
Cerne
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA.
Eric A
EA
Smith
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Cristian
C
Coarfa
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA.
Sean M
SM
Hartig
Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: sean.mcguire@bcm.edu.
Sean E
SE
McGuire
D060565:Argonaute Proteins / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*
D060565:Argonaute Proteins; D051792:Basic Helix-Loop-Helix Proteins; D002868:Chromosomal Proteins, Non-Histone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D035683:MicroRNAs; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C436291:CDKN1B protein, human; C550570:MIRN148 microRNA, human; C094772:centromere protein F