TY - JOUR
T1 - MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer
AU - Baena-Del Valle, Javier A.
AU - Zheng, Qizhi
AU - Esopi, David M.
AU - Rubenstein, Michael
AU - Hubbard, Gretchen K.
AU - Moncaliano, Maria C.
AU - Hruszkewycz, Andrew
AU - Vaghasia, Ajay
AU - Yegnasubramanian, Srinivasan
AU - Wheelan, Sarah J.
AU - Meeker, Alan K.
AU - Heaphy, Christopher M.
AU - Graham, Mindy K.
AU - De Marzo, Angelo M.
N1 - Funding Information:
This study was supported by the NIH/NCI SPORE in Prostate Cancer: P50CA58236, and the NIH/NCI U01 CA196390, the US Department of Defense Prostate Cancer Research Program (PCRP), DoD Award W81XWH-14-2-0182, the Prostate Cancer Bioreposi-tory Network (PCBN), the Prostate Cancer Foundation, and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Experimental and Computational Genomics Core (ECGC) supported by NIH/NCI grant P30 CA006973. We thank ECGC members Anuj Gupta, Alyza Skaist, Paul Schaughency, Jennifer Meyers, and Michael Rongione for their technical support of RNA-seq data collection and processing. We also want to thank Helen Fedor, Marcela Southerland, and Kristen Lecksell for TMA construction and whole slide scanning. We thank Jonathan Coulter, Stefan Barfeld, and Michael Haffner for their valuable insights and help with experimental procedures.
Funding Information:
This study was supported by the NIH/NCI SPORE in Prostate Cancer: P50CA58236, and the NIH/NCI U01 CA196390, the US Department of Defense Prostate Cancer Research Program (PCRP), DoD Award W81XWH-14-2-0182, the Prostate Cancer Biorepository Network (PCBN), the Prostate Cancer Foundation, and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Experimental and Computational Genomics Core (ECGC) supported by NIH/NCI grant P30 CA006973. We thank ECGC members Anuj Gupta, Alyza Skaist, Paul Schaughency, Jennifer Meyers, and Michael Rongione for their technical support of RNA-seq data collection and processing. We also want to thank Helen Fedor, Marcela Southerland, and Kristen Lecksell for TMA construction and whole slide scanning. We thank Jonathan Coulter, Stefan Barfeld, and Michael Haffner for their valuable insights and help with experimental procedures.
Publisher Copyright:
Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - MYC
KW - RNA in situ hybridization
KW - TERC telomerase RNA component
KW - prostate carcinoma
KW - telomerase
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U2 - 10.1002/path.4980
DO - 10.1002/path.4980
M3 - Article
C2 - 28888037
AN - SCOPUS:85039553458
SN - 0022-3417
VL - 244
SP - 11
EP - 24
JO - Journal of Pathology
JF - Journal of Pathology
IS - 1
ER -