Review
Epigenetics: unforeseen regulators in cancer

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Abstract

The past several years have seen a tremendous advance in the understanding of the basic mechanisms of epigenetic regulation. A large number of studies have not only linked epigenetics with cell cycle regulation but also partially unravelled how epigenetics may regulate gene expression. The aim of this review is to provide an overview of the latest findings and current ideas on epigenetics with a focus on emphasizing the emerging influence epigenetics has on the onset and progression of cancer.

Section snippets

Cancer at its basic (Fig. 1)

The decision of whether a cell survives or dies relies heavily on the impact that external factors have on cell cycle progression and programmed cell death pathways. Under normal circumstances, when the environment becomes detrimental to the well-being of a cell, the cell responds either by entering a dormant stage, or by activating programmed cell death pathways. However, it is well known that cells very occasionally do bypass their own natural response and allow uncontrolled proliferation to

Epigenetics and its players

Epigenetic phenomena have been described for many decades. However, not until the past few years have we been able to gather new molecular data geared towards understanding how epigenetic regulation occurs. A noteworthy discovery in this respect involves the concept of ‘cellular memory’. During the development of an organism, initial patterning factors activating specific genes are set forth in the zygote. Eventually these initial factors decay, and the embryo must have a system which allows

PcG and trxG members in cancer (Fig. 2)

The PcG protein family was initially discovered by studies of mutants exhibiting posterior transformation of body segments in Drosophila melanogaster. Since trxG mutants exhibit anterior transformation of body segments, it was hypothesized that these two sets of protein families possess counteracting functions. On the basis of mutant phenotypes, PcG members are thought to maintain repressed gene expression while trxG maintains activated states. The mechanism by which PcG and trxG members

Mixed lineage leukemia

MLL was initially discovered in leukemic patients, who consistently possess translocations between the MLL locus and various fusion partners [20], [21], [22], [23]. MLL was found to be a homolog of the D. melanogaster trithorax protein, and knock-out mutants of MLL were found to be embryonic lethal, after about 10.5 days of development [24], [25]. Since at least 23 different fusion proteins which contain the N-terminal part of MLL are known to date, this portion was speculated to be of great

New roles for PcG and trxG members

PcG and trxG members are classically thought to act only at the chromatin fiber of developmental genes, like homeotic clusters, in maintaining proper gene expression. However, a few years ago, several observations linked for the first time chromatin proteins with cell cycle regulation.

Studies with Bmi-1, the mouse homolog of PSC, first provided evidence that PcG members interact with cell cycle regulators. In Bmi-1 overexpressing mice, two tumor suppressor genes within the ink4a locus were

Modification of proteins as signals?

Modified histones have been known to exist for over three decades. However, their significance was not appreciated until recently. Indeed, a histone code was postulated, stating that different modified positions on histones provide a signal for different epigenetic regulators to bind [62], [63]. A key modification involves the acetylation of histones at defined positions. Characterizations of many complexes possessing acetyltransferase or deacetylase activity have indicated that these

Interfering with enzymatic complexes

Several studies of the past few years collectively support an emerging theme of interference with proper recruitment or with association of deacetylases by oncoproteins. Recruitment of deacetylases was found to be influenced by oncogenic proteins. In a recent report, it was shown that activation of oncogenic Ras results in an increased expression of HDAC4. Interestingly, this increased expression of HDAC4 was found to be associated with an elevated level of kinase activity. Possibly, the kinase

Nucleosome remodelling connecting with cancer

Like the PcG and trxG protein families, nucleosome remodelling enzymes have been found to be conserved across species. The Swi2/Snf2 protein was initially identified in a screen for switch of mating type locus in yeast. Later, homologs in humans, C. elegans, and Drosophila were discovered. Recently, there has been a flurry of reports demonstrating interaction between nucleosome remodelling complexes and cell cycle regulators (for review see [57]). Chromatin remodelling and transcription factor

Conclusion and perspectives (Fig. 3)

The numerous examples of connections between cancer and epigenetic regulation provide a strong foundation for the vital role played by epigenetics in maintaining cell integrity. With the increasing evidence showing that key players of cell regulation must be mutated to give rise to cancer, it becomes an exciting possibility that epigenetic misregulation sensitizes the cell for additional onslaughts giving rise to secondary mutations, and thus leading to tumor progression. The frequent

Acknowledgments

The authors would like to thank Joep Muyrers and Leonie Ringrose for critical reading of the manuscript. We apologize to colleagues whose works were not included due to space limitation. I.M.C. is supported by the National Science Foundation Graduate Fellowship, and R.P. by the Deutsche Forschungsgemeinschaft, the German–Israeli Cooperative Project in Cancer Research, and the Fonds der Chemischen Industrie.

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