The Role of the Estrogen-Related Receptor Alpha (ERRa) in Hypoxia and Its Implications for Cancer Metabolism

• Published in: International journal of molecular sciences Vol. 24; no. 9; p. 7983
• Main Authors: Chaltel-Lima, Leslie, Domínguez, Fabiola, Domínguez-Ramírez, Lenin, Cortes-Hernandez, Paulina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.04.2023; MDPI
• Subjects: Angiogenesis; Cancer; Cell culture; Cell Hypoxia; Dehydrogenases; Energy; Enzymes; ERR; ERRalpha Estrogen-Related Receptor; Estrogen; Estrogens; Gene expression; Genes; Genetic transcription; Glucose; Glycolysis; HIF-independent response to hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Ligands; metabolic adaptation to hypoxia; Metabolism; Neoplasms - genetics; Phenols; Physiology; Proteins; Receptors, Estrogen - metabolism; Review; Survival; Transcription activation; Transcription factors; Transcription Factors - metabolism; Vascular endothelial growth factor; VEGF; Vertebrates; ERR; HIF-independent response to hypoxia; VEGF; angiogenesis; PGC-1α; cancer; metabolic adaptation to hypoxia; ischemia
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24097983

Under low oxygen conditions (hypoxia), cells activate survival mechanisms including metabolic changes and angiogenesis, which are regulated by HIF-1. The estrogen-related receptor alpha (ERRα) is a transcription factor with important roles in the regulation of cellular metabolism that is overexpressed in hypoxia, suggesting that it plays a role in cell survival in this condition. This review enumerates and analyses the recent evidence that points to the role of ERRα as a regulator of hypoxic genes, both in cooperation with HIF-1 and through HIF-1- independent mechanisms, in invertebrate and vertebrate models and in physiological and pathological scenarios. ERRα's functions during hypoxia include two mechanisms: (1) direct ERRα/HIF-1 interaction, which enhances HIF-1's transcriptional activity; and (2) transcriptional activation by ERRα of genes that are classical HIF-1 targets, such as VEGF or glycolytic enzymes. ERRα is thus gaining recognition for its prominent role in the hypoxia response, both in the presence and absence of HIF-1. In some models, ERRα prepares cells for hypoxia, with important clinical/therapeutic implications.