Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers

Abstract The activating TERT promoter mutations and BRAF V600E mutation are well-established oncogenic alterations in human cancers. Coexistence of BRAF V600E and TERT promoter mutations is frequently found in multiple cancer types, and is strongly associated with poor patient prognosis. Although th...

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Autores principales:	Yongxing Wu, Liang Shi, Yuelei Zhao, Pu Chen, Rongrong Cui, Meiju Ji, Nongyue He, Maode Wang, Gang Li, Peng Hou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/8960613512794ea8858c81b1f6b48e74
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spelling	oai:doaj.org-article:8960613512794ea8858c81b1f6b48e742021-12-02T13:43:59ZSynergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers10.1038/s41698-020-00140-52397-768Xhttps://doaj.org/article/8960613512794ea8858c81b1f6b48e742021-01-01T00:00:00Zhttps://doi.org/10.1038/s41698-020-00140-5https://doaj.org/toc/2397-768XAbstract The activating TERT promoter mutations and BRAF V600E mutation are well-established oncogenic alterations in human cancers. Coexistence of BRAF V600E and TERT promoter mutations is frequently found in multiple cancer types, and is strongly associated with poor patient prognosis. Although the BRAFV600E-elicited activation of ERK has been demonstrated to contribute to TERT reactivation by maintaining an active chromatin state, it still remains to be addressed how activated ERK is selectively recruited to mutant TERT promoter. Here, we report that transcription factor GABPA mediates the regulation of BRAFV600E/MAPK signaling on TERT reactivation by selectively recruiting activated ERK to mutant TERT promoter, where activated ERK can phosphorylate Sp1, thereby resulting in HDAC1 dissociation and an active chromatin state. Meanwhile, phosphorylated Sp1 further enhances the binding of GABPA to mutant TERT promoter. Taken together, our data indicate that GABPA and Sp1 synergistically activate mutant TERT promoter, contributing to tumorigenesis and cancer progression, particularly in the BRAFV600E-driven human cancers. Thus, our findings identify a direct mechanism that bridges two frequent oncogenic alterations together in TERT reactivation.Yongxing WuLiang ShiYuelei ZhaoPu ChenRongrong CuiMeiju JiNongyue HeMaode WangGang LiPeng HouNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yongxing Wu Liang Shi Yuelei Zhao Pu Chen Rongrong Cui Meiju Ji Nongyue He Maode Wang Gang Li Peng Hou Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers
description	Abstract The activating TERT promoter mutations and BRAF V600E mutation are well-established oncogenic alterations in human cancers. Coexistence of BRAF V600E and TERT promoter mutations is frequently found in multiple cancer types, and is strongly associated with poor patient prognosis. Although the BRAFV600E-elicited activation of ERK has been demonstrated to contribute to TERT reactivation by maintaining an active chromatin state, it still remains to be addressed how activated ERK is selectively recruited to mutant TERT promoter. Here, we report that transcription factor GABPA mediates the regulation of BRAFV600E/MAPK signaling on TERT reactivation by selectively recruiting activated ERK to mutant TERT promoter, where activated ERK can phosphorylate Sp1, thereby resulting in HDAC1 dissociation and an active chromatin state. Meanwhile, phosphorylated Sp1 further enhances the binding of GABPA to mutant TERT promoter. Taken together, our data indicate that GABPA and Sp1 synergistically activate mutant TERT promoter, contributing to tumorigenesis and cancer progression, particularly in the BRAFV600E-driven human cancers. Thus, our findings identify a direct mechanism that bridges two frequent oncogenic alterations together in TERT reactivation.
format	article
author	Yongxing Wu Liang Shi Yuelei Zhao Pu Chen Rongrong Cui Meiju Ji Nongyue He Maode Wang Gang Li Peng Hou
author_facet	Yongxing Wu Liang Shi Yuelei Zhao Pu Chen Rongrong Cui Meiju Ji Nongyue He Maode Wang Gang Li Peng Hou
author_sort	Yongxing Wu
title	Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers
title_short	Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers
title_full	Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers
title_fullStr	Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers
title_full_unstemmed	Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers
title_sort	synergistic activation of mutant tert promoter by sp1 and gabpa in brafv600e-driven human cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8960613512794ea8858c81b1f6b48e74
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Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAFV600E-driven human cancers

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