MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer.
MicroRNA-101, a tumor suppressor microRNA (miR), is often downregulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2 (enhancer of zeste homolog 2), COX2 (cyclooxygenase-2), POMP (proteasome maturation protein), CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that miR-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to have diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as PLK1 (Polo-like kinase 1), C-MYC, serine-threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 downregulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in prostate cancer, and identifies its regulation and potential downstream therapeutic targets of SUB1 in prostate cancer.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Chakravarthi
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
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Goswami
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
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Pathi
Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Robinson
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
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Cieślik
Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Chandrashekar
Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Agarwal
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
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Siddiqui
Center for Cancer Biostatistics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
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Daignault
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
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Carskadon
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
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Jing
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Urology, University of Michigan, Ann Arbor, MI, USA.|Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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Chinnaiyan
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
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Kunju
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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Palanisamy
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
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Varambally
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; C509201:SUB1 protein, human; D014157:Transcription Factors