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

Abstract

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.

Sleep Apnoea and Cancer: Is There a Relationship?

“…Epigenetic mechanisms that modify genes activity include histone modifications, non-coding RNAs, and DNA methylation. Epigenetic alterations have been associated with hypoxia in cancer and the complex relationship between hypoxia and epigenetic mechanisms have been reviewed elsewhere 46 . Mice engrafted with epithelial lung cancer cells exposed to IH, increased tumour size and invasiveness and hypermethylation of the tumour-promoting Rab3a gene 47 .…”

Gene transcription and chromatin regulation in hypoxia

“…Reduced oxygen can alter chromatin post-translational modifications, both directly via inhibition of oxygendependent enzymes and indirectly through additional mechanisms such as increased expression and/or HIF recruitment to chromatin [8,10,11,[28][29][30][31][32][33].…”

Dynamic Signatures of the Epigenome: Friend or Foe?

“…Of note, many hypoxia and epigenetic pathways are interwoven, as epigenetic modifiers may posttranslationally modify hypoxia-responsive genes affecting their stability. In turn, the hypoxia response regulates the expression of the genes involved in epigenetic signaling [161][162][163]. Epigenetic modifications also play an important role in the acquisition of resistance to various therapies [164,165], including adoptive cell therapy [166].…”