The Methylation Status of the Epigenome: Its Emerging Role in the Regulation of Tumor Angiogenesis and Tumor Growth, and Potential for Drug Targeting

Abstract

Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time display minimal toxic side effects to healthy tissues. Bevacizumab (Avastin)-a humanized monoclonal anti VEGF-A antibody-is now used as anti-angiogenic drug in several forms of cancers, yet with variable results. Recent years brought significant progresses in our understanding of the role of chromatin remodeling and epigenetic mechanisms in the regulation of angiogenesis and tumorigenesis. Many inhibitors of DNA methylation as well as of histone methylation, have been successfully tested in preclinical studies and some are currently undergoing evaluation in phase I, II or III clinical trials, either as cytostatic molecules-reducing the proliferation of cancerous cells-or as tumor angiogenesis inhibitors. In this review, we will focus on the methylation status of the vascular epigenome, based on the genomic DNA methylation patterns with DNA methylation being mainly transcriptionally repressive, and lysine/arginine histone post-translational modifications which either promote or repress the chromatin transcriptional state. Finally, we discuss the potential use of "epidrugs" in efficient control of tumor growth and tumor angiogenesis.

Keywords: DNA methylation; histone methylation; metastasis; tumor angiogenesis.

Figure 1

Potential gene targets for anticancer therapy in DNA methylation-guided cancer progression and metastasis. (o) Tumor formation as a consequence of aberrant DNA methylation in oncogenes and tumor-suppressor genes and further steps of cancer progression: (i) initial metastasis-tumor growth and stimulation of capillary formation, invasion; (ii) metastasis progression-intravasation, invasion of cancer cells through the basal membrane into a blood or lymphatic vessel; (iii) distant metastasis-extravasation, spreading of cancer cells to nearby lymph nodes, tissues, or organs and formation of distant tumors.

Figure 2

Histone methylation, in association to acetylation, regulate the chromatin transcriptional state. Histone lysine/arginine methyltransferases (HMTs), including EZH2, DOTL1 and G9a promote the formation of condensed and transcriptionally repressed chromatin. Histone demethylases (HDMs) in concert with histone acetyltransferases (HATs) and the histone H3K4 methylase SET7 promote the transcriptionally active chromatic state. Histone deacetylases (HDACs) contribute to transcriptional silencing (not discussed in this review).

Figure 3

Schematic anti-cancer mechanism of the targeted therapy based on DNA inhibitors and SAM treatment/positive and negative effects of epidrug action. In the cancer genome, DNA hypermethylation and hypomethylation causes the inactivation of tumor suppressor genes and activation of oncogenes, respectively. DNMT inhibitors block hypermethylation of DNA, hence decreasing methylation the promoters of tumor suppressor genes causing upregulation of their expression. On the other hand, SAM can block the activation of oncogenes and proto-oncogenes. Taken together, the combination of these two agents is likely to combat the DNA abnormalities of gene expression seen in cancer.

Figure 4

Schematic representation of the modifications of histone core proteins methylation status by lysine and arginine methyltransferases/demethylases inhibitors. The methylation status of histones is modified by specific molecules with approved inhibitory abilities verified in multiple in vitro/in vivo studies or tested in clinical trials (the number of trials has been included in brackets) toward lysine and arginine histone methyltransferases/demethylases. Inhibitory, biochemical and biological properties of indicated inhibitors (distinguished by red font) are presented in the main text.