Abstract
Aberrant telomerase reverse transcriptase (TERT) expression is crucial for tumor survival and cancer cells escaping apoptosis. Multiple TERT-locus variants at 5p15 have been discovered in association with cancer risk, yet the underlying mechanisms and clinical impacts remain unclear. Here, our association studies showed that the TERT promoter variant rs2853669 confers a risk of prostate cancer (PCa) in different ethnic groups. Further functional investigation revealed that the allele-specific binding of MYC and E2F1 at TERT promoter variant rs2853669 associates with elevated level of TERT in PCa. Mechanistically, androgen stimulations promoted the binding of MYC to allele T of rs2853669, thereby activating TERT, whereas hormone deprivations enhanced E2F1 binding at allele C of rs2853669, thus upregulating TERT expression. Notably, E2F1 could cooperate with AR signaling to regulate MYC expression. Clinical data demonstrated synergistic effects of MYC/E2F1/TERT expression or with the TT and CC genotype of rs2853669 on PCa prognosis and severity. Strikingly, single-nucleotide editing assays showed that the CC genotype of rs2853669 obviously promotes epithelial–mesenchymal transition (EMT) and the development of castration-resistant PCa (CRPC), confirmed by unbiased global transcriptome profiling. Our findings thus provided compelling evidence for understanding the roles of noncoding variations coordinated with androgen signaling and oncogenic transcription factors in mis-regulating TERT expression and driving PCa.
Highlights
Prostate cancer (PCa) is one of the leading causes of cancer deaths and a highly heritable cancer in men [1]
We found several singlenucleotide polymorphism (SNP) associated with prostate cancer (PCa) risk; among these SNPs, only one SNP named rs2853669 was residing in the functional region
The C allele of rs2853669 was significantly associated with PCa severity observed in Caucasians from UK Biobank whereas T allele was found as a PCa risk allele in Chinese population
Summary
Prostate cancer (PCa) is one of the leading causes of cancer deaths and a highly heritable cancer in men [1]. Genetic heritability was estimated to account for 57% of familial risk in PCa [1]. Identification of genetic loci in association with PCa risk and pathogenesis, and illustration of the underlying mechanisms are expected to have substantial influence on our understanding of PCa and on the prevention and treatment of the disease. Thanks mainly to genome-wide association studies (GWAS), a substantial amount of singlenucleotide polymorphism (SNP) loci have far been identified to be significantly associated with PCa [2]. Even though the detailed functions of several PCa risk SNPs have been unveiled, the regulatory mechanisms underlying many SNPs remain unidentified. Focusing our research scope on PCa, important oncogene-associated risk SNPs might be a way to speed up our understanding of the functions and the risk of SNPs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
