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      MYC drives overexpression of telomerase RNA ( hTR/ TERC) in prostate cancer

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          Abstract

          Telomerase consists of at least two essential elements, an RNA component hTR or TERC that contains the template for telomere DNA addition and a catalytic reverse transcriptase (TERT). While expression of TERT has been considered the key rate-limiting component for telomerase activity, increasing evidence suggests an important role for the regulation of TERC in telomere maintenance and perhaps other functions in human cancer. By using three orthogonal methods including RNAseq, RT-qPCR, and an analytically validated chromogenic RNA in situ hybridization assay, we report consistent overexpression of TERC in prostate cancer. This overexpression occurs at the precursor stage (e.g. high-grade prostatic intraepithelial neoplasia or PIN) and persists throughout all stages of disease progression. Levels of TERC correlate with levels of MYC (a known driver of prostate cancer) in clinical samples and we also show the following: forced reductions of MYC result in decreased TERC levels in eight cancer cell lines (prostate, lung, breast, and colorectal); forced overexpression of MYC in PCa cell lines, and in the mouse prostate, results in increased TERC levels; human TERC promoter activity is decreased after MYC silencing; and MYC occupies the TERC locus as assessed by chromatin immunoprecipitation (ChIP). Finally, we show that knockdown of TERC by siRNA results in reduced proliferation of prostate cancer cell lines. These studies indicate that TERC is consistently overexpressed in all stages of prostatic adenocarcinoma and that its expression is regulated by MYC. These findings nominate TERC as a novel prostate cancer biomarker and therapeutic target.

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          Author and article information

          Journal
          0204634
          5121
          J Pathol
          J. Pathol.
          The Journal of pathology
          0022-3417
          1096-9896
          30 January 2018
          14 November 2017
          January 2018
          07 February 2018
          : 244
          : 1
          : 11-24
          Affiliations
          [1 ]Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
          [2 ]Department of Pathology and Laboratory Medicine, Fundacion Santa Fe De Bogota University Hospital, Bogota, DC, Colombia
          [3 ]Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
          [4 ]Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
          [5 ]Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA
          [6 ]Departments of Urology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
          [7 ]The Brady Urological Research Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
          Author notes
          [* ]Correspondence to: Angelo M De Marzo, Department of Pathology, The Johns Hopkins University School of Medicine, CRB-2/Room 144, 1550 Orleans Street, Baltimore, MD 21231, USA. ademarz@ 123456jhmi.edu
          Article
          PMC5801764 PMC5801764 5801764 nihpa938282
          10.1002/path.4980
          5801764
          28888037
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