Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewEpigenetics: unforeseen regulators in 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.
References (63)
- et al.
Cell
(2000) - et al.
Cell
(1998) - et al.
Cell
(1999) - et al.
Mol. Cell
(2001) - et al.
Curr. Opin. Genet. Dev.
(2001) - et al.
Cell
(1992) - et al.
Cell
(1992) - et al.
Cell
(1996) - et al.
Biochim. Biophys. Acta
(1999) - et al.
Cell
(2000)
Cell
Mol. Cell
Cancer Genet. Cytogenet.
Cell
Genes Dev.
Nature
Genes Dev.
Nature
EMBO J.
Genes Dev.
EMBO J.
EMBO J.
Genetics
EMBO J.
Development
Genetics
Development
Proc. Natl. Acad. Sci. USA
Science
Nature
Cited by (17)
Nanoparticles for tumor targeting
2017, Biopolymer-Based Composites: Drug Delivery and Biomedical ApplicationsNanoparticle therapeutics: Technologies and methods for overcoming cancer
2015, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :Mutations may arise from a combination of environmental and life-style factors but it is difficult to establish a cause–effect relationship. These mutations often affect proteins responsible for the repair of DNA damage, cellular function, cell division and programmed cell death (apoptosis) such as p53; thus, loss of these functions is beneficial for cancer formation and progression [1,5,6]. In normal cells, following DNA damage, several mechanisms are in place to repair the damage, but if the damage cannot be fixed, the cells undergo apoptosis (without inflammation).
Toxicity evaluation of benzo[a]pyrene on the polychaete Perinereis nuntia using subtractive cDNA libraries
2011, Aquatic ToxicologyCitation Excerpt :The transcriptional changes seen in the signaling genes and the genes regulating the metabolism of signaling messengers may have a wide range of effects on transcriptional regulation. Epigenetic modifications such as methylation, acetylation, and phosphorylation, are also factors which play a role in transcriptional regulation and have been known to be involved in the development of cancer (Muyrers-Chen and Paro, 2001). In this study, we found that the transcriptional patterns of DNA methyltransferase, histone methyltransferase, acetyltransferases and phosphate kinases in the polychaete were disturbed by BaP exposure (additional file 1), which might have a wide range of effects on transcription regulation.
RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo
2010, Cancer LettersCitation Excerpt :Despite the advances made over the last decade on cancer therapy, pancreatic cancer appeared to benefit the least in terms of treatment outcome and survival rate. Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group (PcG) proteins, which is one of the several PcG genes being recognized as oncogene [11,12]. EZH2 is known as a related protein of BMI-1, another member of the PcG family, which are both pivotal transcriptional repressors that can regulate gene activity [13].
Identification of novel epithelial stem cell-like cells in human deciduous dental pulp
2009, Biochemical and Biophysical Research CommunicationsCitation Excerpt :It has been reported that p63 expression is associated with proliferative potential in human keratinocytes [23,24]. Bmi-1 is a member of the polycomb group of genes, which have an essential role in embryogenesis and regulation of the cell cycle and lymphopoiesis [25–27]. It is known that Bmi-1 is expressed in hematopoietic stem cells and in stem cells from other tissues [28,29].