Epigenome Research for Elucidation of Cancer and Development of New Drugs
Professor, Graduate School of Medicine, Chiba University
Professor Astushi Kaneda graduated from the Faculty of Medicine (School of Medicine), the University of Tokyo, in 1994. He joined Third Department of Surgery (the current Department of Gastrointestinal Surgery) at the University of Tokyo and became Assistant Professor in 1999. After researches in the National Cancer Center Research Institute and Johns Hopkins University, he was appointed the Associate Professor at the Research Center for Advanced Science and Technology, University of Tokyo, in 2006, promoting the JST PRESTO project and JST CREST project, among others. He was appointed Professor at Department of Molecular Oncology, Graduate School of Medicine, Chiba University, in 2013, and has been promoting AMED's Project for Development of Innovative Research on Cancer Therapeutics since 2014. He is conducting research to elucidate the epigenetic aberrations and molecular mechanisms of oncogenesis of digestive system cancers and other cancers and the epigenetic regulation in the defense mechanisms against cancers for application in cancer diagnosis and treatment.
New drug development through elucidation of "epigenetic aberrations" that cause cancer
What is cancer? The cells that make up our body have a store of encrypted information, which we need in order to live, on the genomic DNA. When abnormality occurs to the encrypted codes, it could lead to a loss of important proteins or generate abnormal proteins that did not exist before. The resultant cells may proliferate abnormally or relocate in other parts of the body. This is what we know as "cancer." Today, comprehensive genomic analyses are being carried out for various types of cancers, and new cancer drugs are being developed based on key genomic abnormalities that have been identified.
Cancers are caused by abnormalities of genomic DNA as mentioned above and also by epigenetic aberrations. Epigenome is attachments to genomic DNA. It can cause methylation of the DNA or modification, by acetylation or methylation, of histone proteins that wrap the DNA. Each cell that makes up a person's body basically has identical genetic DNA codes. The epigenetic attachments, however, differ by types of cells. These attachments mark the genome and tell which genes should be turned on and which genes should be turned off, so as to control the behavior of each cell. If there is abnormality in epigenetic modification, cells would not be able to behave correctly, and this could cause cancer. In fact, epigenetic aberrations have been found in many cancers. For instance, epigenetic aberrations accumulate in the early stages of oncogenesis to heighten the subsequent risk of onset of cancer.
Elucidation of various types of cancers through collaboration among experts in medicine, physics, and pharmacy
Cancers can be broken down into different types. For example, stomach cancer can arise through bacterial infection or through viral infection, in each case the epigenetic aberrations associated with the disease will be different. Therefore, we can categorize different types of cancers, elucidate how key epigenetic aberrations accumulate, and develop drugs that can prevent such accumulations. We can also develop drugs that efficiently rewrite the epigenetic aberrations that have accumulated. Because the genetic DNA codes remain intact in epigenetic aberrations, the cells can regain their correct behavior if the epigenetic modifications can be repaired. In Japan, cancer is a major disease afflicting one in two persons in their lifetimes and causing deaths in a third of the population. We will promote elucidation of cancers and development of new cancer drugs through collaboration among experts in medicine, physics, and pharmacy.
Message to students and young researchers
Epigenome holds the key to understanding not only cancers, but also many other diseases and life phenomena. Join us as we elucidate their molecular mechanisms and develop new drugs.
The group was one of the first to identify large numbers of gene promoter regions affected by aberrant methylation, reporting on the existence of high-methylation gastric cancers and low-methylation gastric cancers. The group subsequently identified that gastric cancers with the most distinct aberrant methylation are induced by EB virus infection. The group is currently carrying out research to elucidate the molecular mechanism of this aberrant methylation (Kaneda et al.).
Colorectal cancers can be categorized into three types depending on the level of aberrant methylation. These differences are also reflected on the morphology of early lesions and on the genetic DNA mutations necessary to bring about oncogenesis (Kaneda et al.).
Ezh2, which is a histone methyltransferase for H3K27, represses the expression of a part of let-7 microRNA target genes and of Lin28b that inhibits the maturation of let-7 target genes. The loss of Ezh2 genes increases the expression of these targets and is involved in the onset of myelodysplastic syndrome (Oshima et al.).
The group created a new mouse model with pancreatic cancer caused by the interaction of KRAS mutation and viral T antigen (Ikehara et al.).
Aggregation of reconstituted nucleosome as a result of binding of linker histone (top). Embryoid body and mouse with loss of Whsc1, a histone methyltransferase for H3K36. Growth inhibition or delay is observable (bottom) (Ura et al.).
The group will develop a method for efficiently synthesizing new molecules. It will create a library of organic molecules that can be subjected to pharmacological activity assessment, and synthesize small molecules acting on epigenetic aberrations (Nemoto et al.).