The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions

Abstract

Cancer is a complex disease resulting from the genetic and epigenetic disruption of normal cells. The mechanistic understanding of the pathways involved in tumor transformation has implicated a priori predominance of epigenetic perturbations and a posteriori genetic instability. In this work, we aimed to explain the mechanistic involvement of epigenetic pathways in the cancer process, as well as the abilities of natural bioactive compounds isolated from medicinal plants (flavonoids, phenolic acids, stilbenes, and ketones) to specifically target the epigenome of tumor cells. The molecular events leading to transformation, angiogenesis, and dissemination are often complex, stochastic, and take turns. On the other hand, the decisive advances in genomics, epigenomics, transcriptomics, and proteomics have allowed, in recent years, for the mechanistic decryption of the molecular pathways of the cancerization process. This could explain the possibility of specifically targeting this or that mechanism leading to cancerization. With the plasticity and flexibility of epigenetic modifications, some studies have started the pharmacological screening of natural substances against different epigenetic pathways (DNA methylation, histone acetylation, histone methylation, and chromatin remodeling) to restore the cellular memory lost during tumor transformation. These substances can inhibit DNMTs, modify chromatin remodeling, and adjust histone modifications in favor of pre-established cell identity by the differentiation program. Epidrugs are molecules that target the epigenome program and can therefore restore cell memory in cancerous diseases. Natural products isolated from medicinal plants such as flavonoids and phenolic acids have shown their ability to exhibit several actions on epigenetic modifiers, such as the inhibition of DNMT, HMT, and HAT. The mechanisms of these substances are specific and pleiotropic and can sometimes be stochastic, and their use as anticancer epidrugs is currently a remarkable avenue in the fight against human cancers.

Keywords: DNMT; HDAC; cancer; cancer therapy; epidrugs; pharmacodynamic.

Figure 1

Cancer development through epigenetic modifications and genetic deregulation due to internal and external factors. External factors (such as oxidative stress, inflammation, and cellular damage) and internal factors (including nutrition, stress, microbes, and drugs) can affect genome and epigenom at different levels. The perturbation of genome (inducing of mutations, translocations, and deletions) and/or epigenom (ectopic methylation and histone modification) can induce homeostasis disruption and therefore cell transformation (cancer). Reproduced with permission from Robert C. Bast Jr., Carlo M. Croce William N. Hait, Waun Ki Hong, Donald W. Kufe, Martine Piccart-Gebart, Raphael E. Pollock, Ralph R. Weichselbaum, Hongyang Wang, and James F. Holland. Holland-Frei Cancer Medicine, 9th Edition; published by John Wiley and Sons, 2016.

Figure 2

Epigenetic modifications. Several epigenetic modifications can inhibit and/or activate gene expression. First mechanism: DNA methylation (inhibited gene expression) is catalyzed by DNMT enzymes and recycled by TET enzymes. This chemical modification is marked at the first time by de novo DNMT during cell differentiation and maintained by DNMT of maintenance during cell division. TET enzymes recycle DNA methylation by their capacity of demethylation. Second mechanism: Histone modifications (inhibit and/or activate gene expression) are mediated by several enzymes and molecular complexes, including HMT, HDM/KDM, HDAC, and HAT. Third mechanism: Remodelage of chromatin which is regulated by nucleosome positioning. Fourth mechanism: mRNA and ncRNA which control gene expression and repression via the upregulation of RNA translation. Abbreviations: DNMT: DNA methyltransferases; HMT: Histone Methyl Transferase; HAT: histone acetyl transferase; HDM: histone demethylases; KDM: Histone Lysine Demethylases; HDAK: Histone Deacetylases.

Figure 3

DNA methylation and demethylation. Methylation of CpG islands promotor region can recruit repressive MBD and impair transcription factor binding. Moreover, methylation of CpG can recruit MeCP2 and therefore SIN3A which can recruit HDAC enzymes that deacetylase histones and therefore condense chromatin (heterochromatin state). In contrary, the demethylation of CpG islands is mediated by TET enzymes creating therefore an euchromatin state (reaction of transcription). Abbreviations: DNMT: DNA methyltransferases; MBD: Methyl-CpG-Binding Domain; TF: Transcriptional Factors; MeCP2: Methyl CpG Binding Protein 2; SiN3A: SIN3: Transcription Regulator Family Member A; HDAC: Histone Deacetylases; TET ten-Eleven Translocation.

Figure 4

Histone modifications. Gene expression can be is switched between repression and expression according to histone modifications. HDAC (histone deacetylase) induces a repression state (chromatin condensed), while HAT (histone transferase) induces an expression state (chromatin decondensed).

Figure 5

Targeted checkpoint of (-)-epigallocatechin-3-O-gallate in cancer disease. EGCG exhibits important anticancer properties via different inhibitory actions of epigenetic enzymes including DNMT, HAT, HDAC, and miRNA. Abbreviations: DNMT: DNA methyltransferase; HAT: histone acetyltransferase; HDAC: histone deacetylase; miRNA: micro-RNA.

Figure 6

The main epigenetic action of stilbenes and ketones. Stilbenes and ketones such as resveratrol and curcumin exhibit inhibitory actions on different epigenetic modifiers including HAT, HDAC, and DNA methyltransferase. Inhibition of epigenetic modifiers decreases cell proliferation, cell growth, invasion and metastasis, and induce apoptosis. Abbreviations. HAT: Histone Acetyltransferase; HDAC: Histone Deacetylase.