AACR Special Conference on Chromatin and Epigenetics in Cancer
The advancements in Next-Generation sequencing technology have recently helped researchers uncover the importance of epigenetic modifying enzymes in many human cancers. Numerous different cancer cells contain mutations in genes that encode histone-modifying enzymes and chromatin-remodeling factors, leading scientists and doctors to conclude that misregulated epigenetic processes are of central importance to cancer biology, and in many cases can be the driving force behind the cancer state. The American Association for Cancer Research (AACR) held a Special Conference in Atlanta, GA, from June 19-22, 2013, on the topic of Chromatin and Epigenetics in Cancer to highlight recent discoveries in this field. The conference was co-organized by Dr. Charles Roberts from the Dana-Farber Cancer Institute in Boston, MA, Dr. Suzanne Baker from St. Jude Children’s Research Hospital in Memphis, TN, and Dr. Gerald Crabtree from Stanford University in Stanford, CA. This meeting brought together many of the leaders in academic and industry research to share their ideas and discoveries to advance the field of epigenetics and cancer. While this meeting was the first of its kind hosted by AACR, the overall success of the sessions and enthusiasm from the attendees suggested that it has the potential to become an annual conference.
The meeting was kicked off by two very impressive keynote talks, one by Dr. Richard Young from the MIT Whitehead Institute for Biomedical Research in Cambridge, MA and the other by Dr. C. David Allis from Rockefeller University in New York, NY. Dr. Young described his latest research on the roles of “Master Transcription Factors”, which are a small group of transcription factors that dominate the control of gene expression programs. In addition to Master Transcription Factors, Dr. Young also discussed “Super Enhancers”, which are cis-acting DNA elements that bind high levels of the Yamanaka factors (such as Oct4, Sox2, and Nanog) and Mediator. Super Enhancers were generally found to be associated with genes that control and define embryonic stem cell identity, and several cancers also show dependence on Super Enhancer activity. Dr. Young’s group went on to demonstrate that certain types of cancer cells are more sensitive to drugs that target Super Enhancers than their normal cell counterparts. The second keynote talk, by Dr. Allis, known for his early work describing and defining the “histone code” and histone variants, focused on the histone variant H3.3. Mutations in both histone H3.3 and the H3.3 chaperone Daxx are associated with different types of cancer. Daxx mutations seen in pancreatic cancer cells have altered histone H3.3 binding, and are unable to bind this histone variant. Additionally, histone H3 K27M mutants found in pediatric brain tumors bind EZH2, the catalytic subunit of the Polycomb repressive complex 2 (PRC2), and inhibit its histone methyltransferase activity. Furthermore, other histone lysine mutants were also shown to inhibit the activity of other histone methyltransferase enzymes. An interesting take away message from this talk was the discovery that phenotypically similar cancers can be grouped into different “epigenetic subgroups” with remarkably different histone mutations, in different parts of the brain, in patients of different ages.
In addition to the keynote presentations, there were many other very exciting and interesting talks at the conference (click here to see the full program of the conference). For example, Dr. Michael Taylor from the Hospital for Sick Children in Toronto, Canada suggested that ependymomas, a type of pediatric brain tumor, do not have any detected genetic mutations, and are therefore possibly caused exclusively by epigenetic mechanisms. Dr. Kristian Helin from the University of Copenhagen in Denmark demonstrated that Polycomb group (PcG) proteins seem to primarily act to maintain silenced genes, as opposed to contributing to de novo gene silencing. Dr. Peter Jones from the University of Southern California in Los Angeles, CA provided interesting data implying that DNA methylation in gene bodies can promote gene expression at certain loci, and treatment with DNA methyltransferase inhibitors, such as 5-Azacytidine, tends to silence the expression of these genes, rather than to activate them. Furthermore, Dr. Jones showed that demethylation of gene bodies is often associated with down-regulating the expression of genes involved in oncogenic metabolic processes, providing a potential mechanism for how a pan-DNA methyltransferase inhibitor could specifically target cancer cells.
Finally, work from Dr. Jesse Smith from Epizyme in Cambridge, MA, Dr. Stuart Schreiber from Harvard and the Broad Institute of Harvard and MIT in Cambridge, MA, and Dr. James Bradner from the Dana-Farber Cancer Institute in Boston, MA describing the development and characterization of novel drugs that target epigenetic processes for use in cancer treatment highlighted the last session of the conference. These final talks emphasized that epigenetic factors are mutated in many different human cancers, and provided hope for the future that these misregulated enzymes are drugable and valid therapeutic targets to help treat cancer. The promising findings presented at this conference suggest that further research exploring the relatively young field describing the connection between epigenetics and cancer will uncover new targets that may ultimately lead to the development of novel treatment strategies.