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

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

Antitumoral properties of butanolic fraction from leaves extract of Chrysobalanus icaco L. in breast and lung cancer cell lines.

Infusion of leaves from Chrysobalanus icaco L., known as Icaco or Abajeru, is widely consumed in Brazil due to its therapeutic effects, such as hyperglycemia regulation, anti-inflammatory, analgesic and against chronic diarrhea. The aqueous and hydroalcoholic extract from Icaco also present anti-cancer properties, including colon cancer and leukemia. However, the antitumoral activity of the butanolic fraction still unknown. This study aimed to investigate the antitumoral properties of butanolic fraction against breast and lung cancer cell lines. Breast and lung cancer cell lines were incubated with the butanolic fraction (0.5, 1 and 5 µg.mL-1) for 24h. WST-1 and Trypan blue exclusion assays evaluated cell viability. The reactive oxygen species generation was measured, and the cell death pathway was analyzed by flow cytometry. The phytochemical profile was determined by thin-layer chromatography (TLC) analysis. The butanolic fraction presents triterpenes, flavonoids, and phenolic compounds as its major constituents. Cell proliferation of MDA-MB-231 and A549 were decreased by butanolic fraction (0.5, 1.0, and 5.0 µg.mL-1) treatment. Butanolic fraction (5.0 µg.mL-1) increase intracellular reactive oxygen species levels in MDA-MB-231, 118%, and in A549, 20%, cell lines. The loss of viability and reactive oxygen species increase was accompanied by apoptosis induction. The cellular migration of both cell lines was decreased by 13% in MDA-MB-231 and by 58% in A549 with the butanolic fraction of C. icaco.  These results suggest that the butanolic fraction from Chrysobalanus icaco has anti-cancer properties against MDA-MB-231 and A549 cancer cells