University of Oulu

Dong X, Zhang Q, Hao J, Xie Q, Xu B, Zhang P, Lu H, Huang Q, Yang T, Wei G-H, Na R and Gao P (2021) Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC. Front. Oncol. 11:754206. doi: 10.3389/fonc.2021.754206

Large multicohort study reveals a prostate cancer susceptibility allele at 5p15 regulating TERT via androgen signaling-orchestrated chromatin binding of E2F1 and MYC

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Author: Dong, Xiaoming1; Zhang, Qin2; Hao, Jinglan1;
Organizations: 1Department of Biochemistry and Molecular Biology, College of Life Sciences, Shaanxi Normal University, Xi’an, China
2Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Fudan University Shanghai Cancer Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
4Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, Department of Animal Science, School of Life Sciences, Shandong University, Qingdao, China
5Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
6Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 15.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022020918387
Language: English
Published: Frontiers Media, 2021
Publish Date: 2022-02-09
Description:

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.

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Series: Frontiers in oncology
ISSN: 2234-943X
ISSN-E: 2234-943X
ISSN-L: 2234-943X
Volume: 11
Article number: 754206
DOI: 10.3389/fonc.2021.754206
OADOI: https://oadoi.org/10.3389/fonc.2021.754206
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
EMT
MYC
Funding: This work was funded by the National Natural Science Foundation of China (81972417 and 82073082), Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Natural Science Foundation of Shaanxi Province (2020JM-292 and 2020JQ-430), Fudan University recruit funds, the “1000 Young Scholars” Program of Shaanxi Province, Fundamental Research Funds for the Central Universities (GK201902002 and GK201903061), and College Students’ Innovative Entrepreneurial Training Plan Program (S202010718091).
Copyright information: © 2021 Dong, Zhang, Hao, Xie, Xu, Zhang, Lu, Huang, Yang, Wei, Na and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
  https://creativecommons.org/licenses/by/4.0/