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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
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