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Regulation Is in the Air: The Relationship between Hypoxia and Epigenetics in Cancer

1
Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro CEP 20231-050, Brazil
2
Laboratório de Biologia do Câncer (LABICAN), Departamento de Biofisica e Biometria (DBB), Instituto de Biologia Roberto Alcântara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro CEP 20511-010, Brazil
3
Programa de Pós-Graduação em Ciências Veterinárias, Universidade Federal do Espírito Santo (UFES), Espírito Santo CEP 29500-000, Brazil
*
Author to whom correspondence should be addressed.
Cells 2019, 8(4), 300; https://doi.org/10.3390/cells8040300
Received: 23 February 2019 / Revised: 22 March 2019 / Accepted: 26 March 2019 / Published: 1 April 2019
(This article belongs to the Special Issue Gene Regulation by HIFs during Hypoxia)
Hypoxia is an inherent condition of tumors and contributes to cancer development and progression. Hypoxia-inducible factors (HIFs) are the major transcription factors involved in response to low O2 levels, orchestrating the expression of hundreds of genes involved in cancer hallmarks’ acquisition and modulation of epigenetic mechanisms. Epigenetics refers to inheritable mechanisms responsible for regulating gene expression, including genes involved in the hypoxia response, without altering the sequence of DNA bases. The main epigenetic mechanisms are DNA methylation, non-coding RNAs, and histone modifications. These mechanisms are highly influenced by cell microenvironment, such as O2 levels. The balance and interaction between these pathways is essential for homeostasis and is directly linked to cellular metabolism. Some of the major players in the regulation of HIFs, such as prolyl hydroxylases, DNA methylation regulators, and histone modifiers require oxygen as a substrate, or have metabolic intermediates as cofactors, whose levels are altered during hypoxia. Furthermore, during pathological hypoxia, HIFs’ targets as well as alterations in epigenetic patterns impact several pathways linked to tumorigenesis, such as proliferation and apoptosis, among other hallmarks. Therefore, this review aims to elucidate the intricate relationship between hypoxia and epigenetic mechanisms, and its crucial impact on the acquisition of cancer hallmarks. View Full-Text
Keywords: hypoxia; hypoxia-inducible factors; epigenetics; DNA methylation; histones modifications; cancer hallmarks hypoxia; hypoxia-inducible factors; epigenetics; DNA methylation; histones modifications; cancer hallmarks
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Camuzi, D.; de Amorim, Í.S.S.; Ribeiro Pinto, L.F.; Oliveira Trivilin, L.; Mencalha, A.L.; Soares Lima, S.C. Regulation Is in the Air: The Relationship between Hypoxia and Epigenetics in Cancer. Cells 2019, 8, 300.

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