Adenosine kinase: An epigenetic modulator in development and disease

Abstract

Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5'-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). The two isoforms are developmentally regulated and are differentially expressed in distinct subcellular compartments with ADK-L localized in the nucleus and ADK-S localized in the cytoplasm. The nuclear localization of ADK-L and its biochemical link to the transmethylation pathway suggest a specific role for gene regulation via epigenetic mechanisms. Recent evidence reveals an adenosine receptor-independent role of ADK in determining the global methylation status of DNA and thereby contributing to epigenomic regulation. Here we summarize recent progress in understanding the biochemical interactions between adenosine metabolism by ADK-L and epigenetic modifications linked to transmethylation reactions. This review will provide a comprehensive overview of ADK-associated changes in DNA methylation in developmental, as well as in pathological conditions including brain injury, epilepsy, vascular diseases, cancer, and diabetes. Challenges in investigating the epigenetic role of ADK for therapeutic gains are briefly discussed.

Keywords: Adenosine kinase; DNA methylation; Development; Epigenetic regulator; Epilepsy.

Figure 1.. Regulation of ADK expression.

a. Tissue-specific regulation of ADK isoforms in adrenal gland, brain, heart, kidney, liver, pancreas, spleen, muscle and thymus is depicted. The signs ++++, +++, ++, + and – denote, very high, high, moderate, low and no expression, respectively. b. Developmental regulation of ADK isoforms in the brain of mice from embryonic (E5 –E20), postnatal (P4–8), and adult stages. c. Localization of ADK-S in the cytoplasm of astrocytes and localization of ADK-L in the nucleus of both astrocytes and neurons in the adult brain. The ADK expression profiles depicted here are schematic representations based on Western blot analyses from previously reported publications (Bjursell et al., 2011; Boison et al., 2002; Cui et al., 2011).

Figure 2.. Molecular, biochemical and epigenetic mechanisms regulated by ADK isoforms.

Schematic shows intracellular adenosine metabolism via ADK-S, equilibration to the extracellular space via equilibrative (ENT) or concentrative (CNT) nucleoside transporters, and associated adenosine receptor-mediated mechanisms. On the other hand, nuclear ADK-L acts as an epigenetic regulator of DNA methylation. ADK-L promotes transmethylation reactions by adenosine conversion to 5’AMP causing a forward shift in S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) transformation, thereby promoting DNA methylation through DNA methyltransferases (DNMT).

Figure 3:. ADK and associated epigenetic mechanisms in pathological conditions.

The epigenetic mechanisms mediated by ADK in various pathological conditions are shown. (i) In brain injury, chronic increase in ADK was associated with increased transmethylation leading to DNA hypermethylation and neurogenesis. The links between methylation changes and cognitive decline need to be investigated. (ii) In experimental epilepsy models, a trigger such as kainic acid induces ectopic overexpression of ADK-L and DNA hypermethylation of a network of genes including PolD1, Polr1e, Rps6kl1, Snrpn, Znf524, Znf541, Znf710. ADK inhibition by 5-ITU and ketogenic diet (KD) was able to restore DNA methylation and prevent onset of seizures. (iii) In preclinical cancer models, studies using transgenic mice with ADK deficiency reveals ADK expression changes in tumors may be associated with methylation of mitogenesis and tumorigenesis genes resulting in increased susceptibility to carcinogen responses and associated mortality. (iv) In β-islet cells in the pancreas, ADK inhibition via genetic or pharmacological tools promoted β-cell proliferation and insulin secretion via MTOR activation.

Figure 4.. ADK mediated epigenetic mechanisms in vascular diseases.

Schematic shows ADK plays an important role as an epigenetic regulator in various vascular pathologies. (i) Hypoxia induces ADK downregulation in endothelial cells, leading to hypomethylation of vascular endothelial growth factor receptor 2 (VEGFR2) and thereby promotes angiogenesis. (ii) In myeloid cells, increase in ADK expression and associated DNA methylation represses the ABCG1 gene, a key regulator of cholesterol trafficking, resulting in the formation of foam cells and atherosclerotic lesions. (iii) In endothelial cells, inflammation (TNF-α)-induced upregulation of ADK promotes histone methylation H3K4 resulting in increased expression of adhesion molecules ICAM-1 and VCAM-1. (iv) In vascular smooth muscle cells (VSMC), ADK expression was associated with DNA hypermethylation and therefore suppression of the KLF4 gene expression, an anti-proliferation gene, resulting in increased VSMC proliferation and neointima formation.