Abstract LB-160: Human telomerase RNA component (hTR/TERC) is consistently overexpressed in prostate cancer, required for cell proliferation and is positively regulated by MYC
Authors: Baena Del Valle Javier A. , Zheng Qizhi , Rubenstein Michael , Meeker Alan K. , Heaphy Christopher M. , Hubbard Gretchen , Bieberich Charles J. , Yegnasubramanian Srinivasan , Esopi David , Wheelan Sarah J. , De Marzo Angelo M. 
Published: July 2016

Introduction: Telomerase activity (TA) is increased in most human cancers (80 - 90%) as a mechanism to maintain telomere function, yet the complex regulatory mechanisms driving TA in different cancer types remain obscure. Telomerase consists of at least two essential elements, a catalytic component (TERT) and an RNA subunit (hTR or TERC). Early data showed that TERC was constitutively expressed at similar levels in different tissues and cancer and that TERT mRNA levels best correlated with enzymatic activity across normal tissues and cancer cells. However, accumulating evidence suggests a more important role for the regulation of TERC in telomere maintenance, as well as possible telomerase activity-independent functions. MYC (c-Myc) is overexpressed in most prostate cancers and is known to regulate TERT mRNA levels in a number of cell types and hence to drive TA. However, there are no prior studies of MYC regulation of TERC. We performed a comprehensive study of TERC expression in cancer cell lines and prostatic tissue, across normal, high grade prostatic intraepithelial neoplasia (PIN), primary carcinomas (PCa), and castrate resistant metastatic disease. We further explored MYC regulation of TERC in Pca and examined cell proliferation in TERC-depleted Pca cell lines.

Experiments and results: Using a novel chromogenic In Situ Hybridization (CISH) RNA assay in FFPE tissues, validated in cell lines by RT-PCR, we found consistent TERC overexpression in nuclei of PIN (p&lt;0.001, N = 26 patients) and Pca cells (p&lt;0.001, N = 66 patients), that was confirmed by qRT-PCR (n = 25) and RNAseq (n = 12) in tumor/benign frozen tissue pairs. There was no association with Gleason score or pathologic stage, and a weak correlation between TERC and TERT levels by RT-PCR. There was a correlation between TERC CISH and MYC protein expression in prostate tissue (Spearman 0.4540, p&lt;0.0001). Further, we show: i) that forced reductions of MYC resulted in decreased TERC levels in 8 cancer cell lines (prostate, lung, breast, and colorectal); ii) MYC occupies the TERC locus by chromatin immunoprecipitation (ChIP); iii) there is a decrease in human TERC promoter activity with MYC silencing; iv) increased Terc levels in PIN and carcinoma in 2 different mouse models of prostate-restricted overexpression of MYC; and v) knockdown of TERC by siRNA resulted in reduced growth and decreased Ki-67 in TERC depleted human prostate cancer cells.

Conclusions: We report consistent overexpression of TERC in PIN and PCa and show the first evidence of MYC regulation of TERC. These studies suggest an important role for MYC-regulated TERC overexpression in human prostate cancer development and progression. Further studies are required to better understand the functional roles of TERC (e.g. TA mediated vs. other activity) in carcinogenesis of the prostate and other organ sites and its regulation by MYC.

Citation Format: Javier A. Baena Del Valle, Qizhi Zheng, Michael Rubenstein, Alan K. Meeker, Christopher M. Heaphy, Gretchen Hubbard, Charles J. Bieberich, Srinivasan Yegnasubramanian, David Esopi, Sarah J. Wheelan, Angelo M. De Marzo. Human telomerase RNA component (hTR/TERC) is consistently overexpressed in prostate cancer, required for cell proliferation and is positively regulated by MYC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-160.