Histone Modifying Enzymes as Targets for Therapeutic Intervention in Oesophageal Adenocarcinoma

Abstract

Oesophageal adenocarcinoma (OAC) has a dismal prognosis, where curable disease occurs in less than 40% of patients, and many of those with incurable disease survive for less than a year from diagnosis. Despite the widespread use of systematic chemotherapy in OAC treatment, many patients receive no benefit. New treatments are urgently needed for OAC patients. There is an emerging interest in epigenetic regulators in cancer pathogenesis, which are now translating into novel cancer therapeutic strategies. Histone-modifying enzymes (HMEs) are key epigenetic regulators responsible for dynamic covalent histone modifications that play roles in both normal and dysregulated cellular processes including tumorigenesis. Several HME inhibitors are in clinical use for haematological malignancies and sarcomas, with numerous on-going clinical trials for their use in solid tumours. This review discusses the current literature surrounding HMEs in OAC pathogenesis and their potential use in targeted therapies for this disease.

Keywords: EZH2; HDAC; biomarker; epigenetics; histone modifying enzymes; oesophageal cancer.

Figure 1

Potential effects of HMEi in the tumour microenvironment. The TME is comprised of numerous cell types which are crucial in promoting tumorigenesis and drug resistance but may be uniquely susceptible to HMEi. EZH2: Enhancer of zeste homolog 2, HDAC: histone deacetylase, TAM: Tumour associated macrophage, CAF: Cancer associated fibroblast, MDSC: myeloid-derived suppressor cells, NK cell: Natural Killer cell. Red arrow: downregulation/inhibition, Green arrow: upregulation. (Created with BioRender.com, accessed on 27 June 2021).