Dr. Ron’s Research Review – October 19, 2011

This week’s research review: Epigenetics

Epigenetics is defined as heritable changes in gene expression that are, unlike mutations, not attributable to alterations in the sequence of DNA.

The predominant epigenetic mechanisms are DNA methylation, modifications to chromatin, loss of imprinting and non-coding RNA.

Autoimmunity

Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. (Meda, Folci et al. 2011) (Renaudineau and Youinou 2011)

Sulforaphane

Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. Sulforaphane mediates epigenetic down-regulation of telomerase in breast cancer prevention. (Meeran, Patel et al. 2010)

Curcumin

Accumulating data support curcumin's functionality in modulating multiple biological processes at low concentrations through its activity as an epigenetic agent. As an epigenetic agent, curcumin had novel mechanisms through its interaction with histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and microRNAs. (Fu and Kurzrock 2010) (Reuter, Gupta et al. 2011)

Dr. Ron


Articles

Development of curcumin as an epigenetic agent

            (Fu and Kurzrock 2010) Download

The clinical benefits of curcumin as a single agent were demonstrated in patients with advanced pancreatic cancer in a phase 2 study despite pharmacokinetic analysis showing a much lower plasma concentration of curcumin in humans than in vitro. The diverse and broad biological activities of curcumin are mediated through direct interaction of curcumin with target proteins as well as epigenetic modulation of target genes, supported by evidence that curcumin modulates gene expression in a time- and concentration-dependent manner in human cancer cells. This review delineates the novel mechanisms of curcumin as an epigenetic agent through its interaction with histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and microRNAs. Accumulating data support curcumin's functionality in modulating multiple biological processes at low concentrations through its activity as an epigenetic agent. The development of curcumin as an epigenetic agent warrants further preclinical and clinical studies to explore its diversity and efficacy in cancer treatment and in combination with other anticancer agents.

The epigenetics of autoimmunity

         (Meda, Folci et al. 2011) Download

The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years, several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases.

Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines

            (Meeran, Patel et al. 2010) Download

BACKGROUND: Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer. PRINCIPAL FINDINGS: We found that SFN significantly inhibits the viability and proliferation of breast cancer cells in vitro while it has negligible effects on normal breast cells. Inhibition of telomerase has received considerable attention because of its high expression in cancer cells and extremely low level of expression in normal cells. SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. Down-regulation of DNMTs in response to SFN induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression. Chromatin immunoprecipitation (ChIP) analysis of the hTERT promoter revealed that SFN increased the level of active chromatin markers acetyl-H3, acetyl-H3K9 and acetyl-H4, whereas the trimethyl-H3K9 and trimethyl-H3K27 inactive chromatin markers were decreased in a dose-dependent manner. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins such as MAD1 and CTCF to the hTERT regulatory region. Depletion of CTCF using siRNA reduced the SFN-induced down-regulation of hTERT mRNA transcription in these breast cancer cells. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast cancer cells. SIGNIFICANCE: Collectively, our results provide novel insights into SFN-mediated epigenetic down-regulation of telomerase in breast cancer prevention and may open new avenues for approaches to SFN-mediated cancer prevention.

Epigenetics and autoimmunity, with special emphasis on methylation

            (Renaudineau and Youinou 2011) Download

Epigenetics signifies stable and heritable changes in gene expression without changes in the genetic code. There is a wealth of emerging evidence for such processes in promoting autoimmunity. The first clue is that inhibition of DNA methyl transferases (DNMTs) induces systemic lupus erythematosus (SLE) in animals. Similar immune-mediated disorders have been generated by injecting normal T cells incubated with DNMT inhibitors into healthy mice. Further, monozygotic twins display differences in DNA methylation that parallel discordances in SLE. Moreover, defects in DNA methylation characterize lymphocytes from SLE, synoviocytes from rheumatoid arthritis, and neural cells from multiple sclerosis patients. It has also been shown that DNA hypomethylation of T and B cells correlates with reduced DNMT efficacy and histone acetylation in SLE. Once a gene promoter has been demethylated, the gene recovers its capacity to be transcribed, e.g., genes for cytokines, activation receptors on cells, and endogenous retroviruses. This outcome has been associated with a blockage of the Erk pathway and/or a growth arrest at the G0/G1 interface of the cell cycle. Of importance is the fact that these changes can be reversed. For example, blockade of the interleukin-6 autocrine loop in SLE B cells restores DNA methylation status, thus opening new perspectives for therapy.

Epigenetic changes induced by curcumin and other natural compounds

            (Reuter, Gupta et al. 2011) Download

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.


References

Fu, S. and R. Kurzrock (2010). "Development of curcumin as an epigenetic agent." Cancer 116(20): 4670-6.

Meda, F., M. Folci, et al. (2011). "The epigenetics of autoimmunity." Cell Mol Immunol 8(3): 226-36.

Meeran, S. M., S. N. Patel, et al. (2010). "Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines." PLoS One 5(7): e11457.

Renaudineau, Y. and P. Youinou (2011). "Epigenetics and autoimmunity, with special emphasis on methylation." Keio J Med 60(1): 10-6.

Reuter, S., S. C. Gupta, et al. (2011). "Epigenetic changes induced by curcumin and other natural compounds." Genes Nutr 6(2): 93-108.