Cargando…
Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC
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 assoc...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631195/ https://www.ncbi.nlm.nih.gov/pubmed/34858826 http://dx.doi.org/10.3389/fonc.2021.754206 |
_version_ | 1784607504008740864 |
---|---|
author | Dong, Xiaoming Zhang, Qin Hao, Jinglan Xie, Qianwen Xu, Binbing Zhang, Peng Lu, Haicheng Huang, Qilai Yang, Tielin Wei, Gong-Hong Na, Rong Gao, Ping |
author_facet | Dong, Xiaoming Zhang, Qin Hao, Jinglan Xie, Qianwen Xu, Binbing Zhang, Peng Lu, Haicheng Huang, Qilai Yang, Tielin Wei, Gong-Hong Na, Rong Gao, Ping |
author_sort | Dong, Xiaoming |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8631195 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86311952021-12-01 Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC Dong, Xiaoming Zhang, Qin Hao, Jinglan Xie, Qianwen Xu, Binbing Zhang, Peng Lu, Haicheng Huang, Qilai Yang, Tielin Wei, Gong-Hong Na, Rong Gao, Ping Front Oncol Oncology 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. Frontiers Media S.A. 2021-11-10 /pmc/articles/PMC8631195/ /pubmed/34858826 http://dx.doi.org/10.3389/fonc.2021.754206 Text en Copyright © 2021 Dong, Zhang, Hao, Xie, Xu, Zhang, Lu, Huang, Yang, Wei, Na and Gao https://creativecommons.org/licenses/by/4.0/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. |
spellingShingle | Oncology Dong, Xiaoming Zhang, Qin Hao, Jinglan Xie, Qianwen Xu, Binbing Zhang, Peng Lu, Haicheng Huang, Qilai Yang, Tielin Wei, Gong-Hong Na, Rong Gao, Ping Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC |
title | Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC |
title_full | Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC |
title_fullStr | Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC |
title_full_unstemmed | Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC |
title_short | Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC |
title_sort | large multicohort study reveals a prostate cancer susceptibility allele at 5p15 regulating tert via androgen signaling-orchestrated chromatin binding of e2f1 and myc |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631195/ https://www.ncbi.nlm.nih.gov/pubmed/34858826 http://dx.doi.org/10.3389/fonc.2021.754206 |
work_keys_str_mv | AT dongxiaoming largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT zhangqin largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT haojinglan largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT xieqianwen largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT xubinbing largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT zhangpeng largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT luhaicheng largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT huangqilai largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT yangtielin largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT weigonghong largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT narong largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc AT gaoping largemulticohortstudyrevealsaprostatecancersusceptibilityalleleat5p15regulatingtertviaandrogensignalingorchestratedchromatinbindingofe2f1andmyc |