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

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.

Journal

Journal ID (nlm-journal-id): 0204634

Journal ID (pubmed-jr-id): 5121

Journal ID (nlm-ta): J Pathol

Journal ID (iso-abbrev): J. Pathol.

Title: The Journal of pathology

ISSN (Print): 0022-3417

ISSN (Electronic): 1096-9896

Publication date Nihms-submitted: 30 January 2018

Publication date (Electronic): 14 November 2017

Publication date (Print): January 2018

Publication date PMC-release: 07 February 2018

Volume: 244

Issue: 1

Pages: 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

Accession ID: PMC5801764 Pmcid ID: PMC5801764 Pmc-uid ID: 5801764 Manuscript ID: nihpa938282

DOI: 10.1002/path.4980

PMC ID: 5801764

PubMed ID: 28888037

Categories

Subject: Article