ERK signaling controls productive HIF-1 binding to chromatin and cancer cell adaptation to hypoxia through HIF-1α interaction with NPM1
Datum
2021Language
en
Schlagwort
Zusammenfassung
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. © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Collections
Verwandte Dokumente
Anzeige der Dokumente mit ähnlichem Titel, Autor, Urheber und Thema.
-
Hypoxia-induced Changes in SUMO Conjugation Affect Transcriptional Regulation under Low Oxygen
Chachami G., Stankovic-Valentin N., Karagiota A., Basagianni A., Plessmann U., Urlaub H., Melchior F., Simos G. (2019)Hypoxia occurs in pathological conditions, such as cancer, as a result of the imbalance between oxygen supply and consumption by proliferating cells. HIFs are critical molecular mediators of the physiological response to ... -
Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia
Mylonis I., Kourti M., Samiotaki M., Panayotou G., Simos G. (2017)Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; ... -
Hypoxia upregulates integrin gene expression in microvascular endothelial cells and promotes their migration and capillary-like tube formation
Befani C., Liakos P. (2017)Tissue hypoxia affects gene expression through the hypoxia-inducible transcription factors, HIF-1 and HIF-2, in both physiological and pathological angiogenesis. Angiogenesis is a complex response of endothelial cells ...