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...

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Autores principales:	Xiaoming Dong, Qin Zhang, Jinglan Hao, Qianwen Xie, Binbing Xu, Peng Zhang, Haicheng Lu, Qilai Huang, Tielin Yang, Gong-Hong Wei, Rong Na, Ping Gao
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	TERT rs2853669 prostate cancer E2F1 MYC AR signaling Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/53103bcead54426d874775057ac00f58
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spelling	oai:doaj.org-article:53103bcead54426d874775057ac00f582021-11-10T05:29:50ZLarge Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC2234-943X10.3389/fonc.2021.754206https://doaj.org/article/53103bcead54426d874775057ac00f582021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.754206/fullhttps://doaj.org/toc/2234-943XAberrant 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.Xiaoming DongQin ZhangJinglan HaoQianwen XieBinbing XuPeng ZhangHaicheng LuQilai HuangTielin YangGong-Hong WeiGong-Hong WeiRong NaPing GaoFrontiers Media S.A.articleTERTrs2853669prostate cancerE2F1MYCAR signalingNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TERT rs2853669 prostate cancer E2F1 MYC AR signaling Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	TERT rs2853669 prostate cancer E2F1 MYC AR signaling Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Xiaoming Dong Qin Zhang Jinglan Hao Qianwen Xie Binbing Xu Peng Zhang Haicheng Lu Qilai Huang Tielin Yang Gong-Hong Wei Gong-Hong Wei Rong Na Ping Gao Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC
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	article
author	Xiaoming Dong Qin Zhang Jinglan Hao Qianwen Xie Binbing Xu Peng Zhang Haicheng Lu Qilai Huang Tielin Yang Gong-Hong Wei Gong-Hong Wei Rong Na Ping Gao
author_facet	Xiaoming Dong Qin Zhang Jinglan Hao Qianwen Xie Binbing Xu Peng Zhang Haicheng Lu Qilai Huang Tielin Yang Gong-Hong Wei Gong-Hong Wei Rong Na Ping Gao
author_sort	Xiaoming Dong
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_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_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_sort	large multicohort study reveals a prostate cancer susceptibility allele at 5p15 regulating tert via androgen signaling-orchestrated chromatin binding of e2f1 and myc
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/53103bcead54426d874775057ac00f58
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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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