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.

In perspective: An update on telomere targeting in cancer

“…More specifically, h TERC has been shown to be overexpressed in all phases of prostate carcinogenesis, as well as linked to the oncogene, MYC . Specifically, when MYC was reduced h TERC levels temporarily decreased, while during MYC overexpression, h TERC levels increased . This correlation was not limited to prostate carcinogenesis, and instead was replicated in the same study using a non–small‐cell carcinoma cell line (NCI‐H23), a breast cancer cell line (MCF‐7), and a colorectal carcinoma cell line (DLD‐1) .…”

“…Specifically, when MYC was reduced h TERC levels temporarily decreased, while during MYC overexpression, h TERC levels increased . This correlation was not limited to prostate carcinogenesis, and instead was replicated in the same study using a non–small‐cell carcinoma cell line (NCI‐H23), a breast cancer cell line (MCF‐7), and a colorectal carcinoma cell line (DLD‐1) . Again, the mechanism is not fully understood albeit the knock‐down of h TERC limited telomerase activity, highlighting its importance in immortalizing cells via telomere maintenance and elongation pathways.…”

“…While the specific contribution of h TERC is largely unknown, it was previously noted that suppression of h TERC in a large panel of cancer cells including lymphoma, melanoma, bladder, breast, and colorectal carcinoma inhibited growth and led to apoptosis . More specifically, h TERC has been shown to be overexpressed in all phases of prostate carcinogenesis, as well as linked to the oncogene, MYC . Specifically, when MYC was reduced h TERC levels temporarily decreased, while during MYC overexpression, h TERC levels increased .…”

Current Perspectives of Telomerase Structure and Function in Eukaryotes with Emerging Views on Telomerase in Human Parasites

“…Melanoma, skin carcinoma and liver cancer have highest frequencies of TERT promoter mutations while gastric cancer, pancreatic cancer and gastrointestinal stromal cancer reported to have lower frequency of these mutations [ 173 , 176 , 177 ]. In prostate cancer cells, expression of both hTER and hTERT are found to be directly correlated to the expression of myelocytomatosis viral oncogene (MYC) as silencing of the later results in decreased expression of hTER thus causing reduced cell proliferation [ 178 ]. The exact mechanism of this correlation is still under investigation but it is thought that mutations in the hTERT promoter enhances the binding of MYC via the increased binding of ETS/T-cell factor (TCF) [ 179 ].…”

The Unforeseen Non-Coding RNAs in Head and Neck Cancer

“…The first one represents a reverse transcriptase (TERT) that has a catalytic unit associated and the other one is the TERC. TERC is a RNA template from which the missing part of the DNA is synthetized [ 106 ]. TERC was first discovered in eukaryotic cells.…”