ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1

The hypoxia‐inducible factor HIF‐1 is essential for oxygen homeostasis. Despite its well‐understood oxygen‐dependent expression, regulation of its transcriptional activity remains unclear. We show that phosphorylation by extracellular signal‐regulated kinases1/2 (ERK1/2), in addition to promoting HI...

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Autores principales:	Kreon Koukoulas, Antonis Giakountis, Angeliki Karagiota, Martina Samiotaki, George Panayotou, George Simos, Ilias Mylonis
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cancer HIF hypoxia NPM1 nucleophosmin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/96b5fdc018014ecb9f0b7ff7a70f7dfc
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spelling	oai:doaj.org-article:96b5fdc018014ecb9f0b7ff7a70f7dfc2021-12-02T10:31:06ZERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM11878-02611574-789110.1002/1878-0261.13080https://doaj.org/article/96b5fdc018014ecb9f0b7ff7a70f7dfc2021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13080https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261The hypoxia‐inducible factor HIF‐1 is essential for oxygen homeostasis. Despite its well‐understood oxygen‐dependent expression, regulation of its transcriptional activity remains unclear. We show that phosphorylation by extracellular signal‐regulated kinases1/2 (ERK1/2), in addition to promoting HIF‐1α nuclear accumulation, also enhances its interaction with chromatin and stimulates direct binding to nucleophosmin (NPM1), a histone chaperone and chromatin remodeler. NPM1 is required for phosphorylation‐dependent recruitment of HIF‐1 to hypoxia response elements, its interaction with acetylated histones, and high expression of HIF‐1 target genes under hypoxia. Transcriptome analysis revealed a significant number of hypoxia‐related genes commonly regulated by NPM1 and HIF‐1. These NPM1/HIF‐1α co‐upregulated genes are enriched in three different cancer types, and their expression correlates with hypoxic tumor status and worse patient prognosis. In concert, silencing of NPM1 expression or disruption of its association with HIF‐1α inhibits metabolic adaptation of cancer cells and triggers apoptotic death upon hypoxia. We suggest that ERK‐mediated phosphorylation of HIF‐1α regulates its physical interaction with NPM1, which is essential for the productive association of HIF‐1 with hypoxia target genes and their optimal transcriptional activation, required for survival under low oxygen or tumor growth.Kreon KoukoulasAntonis GiakountisAngeliki KaragiotaMartina SamiotakiGeorge PanayotouGeorge SimosIlias MylonisWileyarticlecancerHIFhypoxiaNPM1nucleophosminNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3468-3489 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer HIF hypoxia NPM1 nucleophosmin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cancer HIF hypoxia NPM1 nucleophosmin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kreon Koukoulas Antonis Giakountis Angeliki Karagiota Martina Samiotaki George Panayotou George Simos Ilias Mylonis ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1
description	The hypoxia‐inducible factor HIF‐1 is essential for oxygen homeostasis. Despite its well‐understood oxygen‐dependent expression, regulation of its transcriptional activity remains unclear. We show that phosphorylation by extracellular signal‐regulated kinases1/2 (ERK1/2), in addition to promoting HIF‐1α nuclear accumulation, also enhances its interaction with chromatin and stimulates direct binding to nucleophosmin (NPM1), a histone chaperone and chromatin remodeler. NPM1 is required for phosphorylation‐dependent recruitment of HIF‐1 to hypoxia response elements, its interaction with acetylated histones, and high expression of HIF‐1 target genes under hypoxia. Transcriptome analysis revealed a significant number of hypoxia‐related genes commonly regulated by NPM1 and HIF‐1. These NPM1/HIF‐1α co‐upregulated genes are enriched in three different cancer types, and their expression correlates with hypoxic tumor status and worse patient prognosis. In concert, silencing of NPM1 expression or disruption of its association with HIF‐1α inhibits metabolic adaptation of cancer cells and triggers apoptotic death upon hypoxia. We suggest that ERK‐mediated phosphorylation of HIF‐1α regulates its physical interaction with NPM1, which is essential for the productive association of HIF‐1 with hypoxia target genes and their optimal transcriptional activation, required for survival under low oxygen or tumor growth.
format	article
author	Kreon Koukoulas Antonis Giakountis Angeliki Karagiota Martina Samiotaki George Panayotou George Simos Ilias Mylonis
author_facet	Kreon Koukoulas Antonis Giakountis Angeliki Karagiota Martina Samiotaki George Panayotou George Simos Ilias Mylonis
author_sort	Kreon Koukoulas
title	ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1
title_short	ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1
title_full	ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1
title_fullStr	ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1
title_full_unstemmed	ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1
title_sort	erk signaling controls productive hif‐1 binding to chromatin and cancer cell adaptation to hypoxia through hif‐1α interaction with npm1
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/96b5fdc018014ecb9f0b7ff7a70f7dfc
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ERK signaling controls productive HIF‐1 binding to chromatin and cancer cell adaptation to hypoxia through HIF‐1α interaction with NPM1

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