Mechanisms underlying epigenetically mediated gene silencing in cancer
Introduction
The very existence of this journal issue, and the list of topics and contributing experts, attests to the remarkable increase in awareness and interest in epigenetic changes which contribute to the genesis and progression of human cancer. The important nature, alone, of the genes which can be silenced in the absence of coding region mutations1., 2. (and chapters within this issue), is ample testimony to our need to understand the mechanisms underlying the chromatin changes which mediate these events. In reality, we are at a very early stage for unraveling the precise steps through which aberrant loss of gene transcription, and the often associated abnormalities of promoter methylation, are established during tumor progression. We are better beginning to understand the events in chromatin formation, and their interaction with DNA methylation, that directly mediate abnormal transcriptional repression of key genes. In this chapter we will consider what is being learned in each of these areas and where the lines of investigation may be going. The last several years alone have seen many surprises in the field and breaking of established paradigms and more are sure to follow.
Section snippets
CpG islands—patterns and timing of methylation in cancer
The aberrant promoter CpG island methylation in cancer can, perhaps, best be viewed as conversion of a transcriptionally active to a transcriptionally repressive chromatin domain. As such, these events are a microcosm of a balance that must be maintained for the entire mammalian genome. In this balance, a prime role of DNA methylation may be to lock in the transcriptionally repressed state, which characterizes the majority of our DNA, or bulk heterochromatin.3 This prevention of transcription
The chromatin constitution of gene silencing in cancer
While much remains unknown about the molecular boundaries which protect CpG islands from promoter methylation, more is becoming known about mechanisms through which this change is functionally linked to gene silencing. The information is far from complete particularly as it relates to specific genes, but ongoing investigations in basic mechanisms of transcriptional repression are paying dividends for understanding epigenetic changes in cancer.
Figure 2 depicts how we may envision the composition
The derivation of hypermethylated and silenced gene promoters in cancer
One of the most intriguing and important questions in the field of aberrant gene silencing in cancer is what are the molecular events that lead to this process during tumor progression in the first place? The answers would obviously tie together many of the components that have been discussed so far and may also provide critical insights into tumor biology. We are just beginning to gain insights into this problem.
DNA methylation in the mammalian genome is catalyzed by at least three
Conclusions
More and more evidence continues to point towards epigenetic alterations in general, and gene silencing events in particular, as fundamental aspects of tumorigenesis. It is then becoming paramount to understand the molecular events which mediate the events and lead to their establishment. The current review has attempted to briefly outline the status of this field. Hopefully, the exciting recent progress towards these research goals is apparent, as is the need to go much further. Aberrant gene
Acknowledgements
The author thanks all the many colleagues, and especially his long time partner in many methylation studies, James Herman, who have contributed to his perspective on the subject reviewed and all those authors whose work has contributed to the review. Apologies are extended to those investigators whose work is not directly cited due to space limitations, but whose work is found throughout the reviews and primary papers that have been included. Portions of work referred to that were performed in
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