Can epigenetics quench the thirst of scientists?

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By: Kenneth Ting

Scientists are always thirsty. Their thirst however, is not quenched by streams of water trickling from the mountain. It is satisfied by the flow of information transmitted from a new pool of knowledge. In 1990, researchers have quenched their thirst by launching the Human Genome Project (HGP), thereby enabling scientists to dissect the human genome organization1, 2. However, after a decade had passed, scientists were thirsty again as they realized HGP did not always correlate genes with diseases that do not arise from a clear cut genetic reason, such as cancer 3. As a result, current researchers in cancer biology are desperately looking for a new fountain of knowledge to slake their thirst, and fortunately they found one – epigenetics, the study of how gene expression is regulated without changing the sequence of DNA4, 5. Among all the areas in epigenetics, histone modifications, is one of the most important fields of epigenetics that is contributing to the development of new biomarkers and therapeutics for cancer, suggesting more emphasis should be placed on this field in the following decades.

It is long known that DNA is coiled around histones, and thereby its accessibility to other cofactors and enhancers is heavily influenced by the configuration of histones6. Hence, modifying the histones arrangement can influence gene transcription6. Among all of the enzymes that catalyze histone modification, research has shown that the malfunctioning of PcG enchancer of zeste homolog 2 (EZH2) plays an indisputable role in a variety of cancers, and its inactivation also shows promising therapeutic effects against cancer7.

According to the hierarchical model of PRC recruitment, EZH2 will catalyze a tri-methylation on histone3 lysine27 (H3K27) upon its recruitment8. This tri-methylation will then subsequently recruit the PRC1 complex to catalyze a monoubiquitination on histone H2A lysine119 (H2AK119), thereby blocking RNAPII from transcribing the targeted gene8. Intuitively, one can imagine that an overexpression of EZH2 can easily lead to cancer if EZH2 represses tumor suppressing genes’ expression, and as expected, it does indeed9. In prostate cancer for instance, overexpression of EZH2 represses tumor suppressing genes, such as Disabled Homolog2-Interacting Protein (DAB2IP) and adrenergic receptor beta-2 (ADRB2)10.  The repression of DAB2IP promotes Ras and NF-kB to initiate prostate tumor formation and metastasis, while repressing ADRB2 promotes prostate epithelial cells undergoing epithelial-mesenchymal transition10, 11.

Hence, as evidently displayed from past experimental results, EZH2 has great potential to serve as a biological marker for a variety of cancers. In fact, the inhibition of EZH2 can be used as a target for cancer therapeutics. For example, past research has illustrated that DZNep, a molecule that induces the degradation of EZH2, inhibits cell growth and tumor formation12. Pharmaceutical companies, such as Epizyme Inc. and GlaxoSmithKline plc., also have already shown that inhibitors of EZH2 are effective against lymphoma in preclinical models. These inhibitors will be taken to clinical trials in the near future, again suggesting that EZH2, and possibly other histone modifying enzymes, can serve as biological markers for cancer, and valid targets for cancer therapeutics.

Scientists are always thirsty, fortunately, years of searching has led to the discovery of a new body of knowledge – epigenetics. Without a doubt, aberrations of epigenetic machinery play a vital role in cancer, and signs of initial development of biomarkers and cancer therapeutics based on epigenetic modifications are presently on the rise. Considering the importance of epigenetics in cancer biology, especially histone modifications, it is time to draw more emphasis to this area. It is time to open up to the possibilities of adjusting our sails, and steer towards a different destination.

References:

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  3. Williams, S. C. Epigenetics. Proc. Natl. Acad. Sci. USA 2013; 110, 3209
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