UST Science & Technology Report

Marking Neon Signs in Cancer Cells

“Cancer cells try to save energy for their own reproduction by not wasting energy on something they really don’t need”, Professor Ming-Ta Hsu, National Yang-Ming University.

Genomics and brain science represent the two major research endeavors in biology in the 21th century. These two scientific fields were chosen by National Yang-Ming University (NYMU) as the research programs in the Aim for Top University Program. According to Professor Ming-Ta Hsu of NYMU which is a partner university of the University System of Taiwan, his institution started genomic research in 1995 soon after US started the Human Genome Project in 1990. In collaboration with Veteran General Hospital Taipei, the research focus was first on the human chromosome 4q region which has been implicated in liver cancer. The Yang Ming Genome Center (YMGC) then participated in several international sequencing projects including chimpanzee, rice and Streptomyces genome sequencing as well as sequencing fungus and bacterial pathotgens in Taiwan and became an internationally well-recognized genome center.

In view of the importance of epigenetic regulation in the post-genomic period, Prof. T.-M. Hsu and his colleagues have started preparing for this new discipline in 2001 and in 2006 proposed the study of human epigenomics in the Aim for Top University Project funded by Ministry of Education. Epigenetic regulation is a short term (as contrast to long term evolutionary changes) heritable strategy to modify the genome in response to environmental challenges. This is an important strategy since a genome with fixed nucleotide sequence cannot deal with myriad of environmental challenges to cells and organism during the lifetime. Genome is like a complex society of genes—it needs sophisticated regulatory agencies to coordinate thousands of genes to make things function properly and avoid chaos. These complicated epigenetic modifications on genome are just like neon signs that direct the regulatory machinery of cells to the sites of genes that need to be controlled and coordinated in response to specific situations that require some genes to be activated, silenced or altered in their functions. The YMGC researchers investigated how these regulatory neon signs are organized and how the regulatory machineries read the signs and coordinates the genes. The first epigenetic mark studied is the methylation of DNA resulting in the subtle alteration of gene expression program. One interesting result found by them is that cancer cells do not methylate their genome in areas that either have no genes or contain genes they don’t need. Since methylation modification requires energy, the implication of their finding is that cancer cells try to save energy for their own reproduction by not wasting energy on something they really don’t need. This fact could be exploited to identify tumor cells.

Another interesting finding is that there are many genes that do not conform to the current known rule that methylation at the promoter (the major regulated site for expression of a gene) would suppress gene expression. In fact there are many genes with opposite behavior. This can be rationalized by the argument that methylation could Inhibit either the binding of activator (resulting in gene silencing) or inhibitor (resulting in gene activation). Analysis of DNA methylation in mouse tissues and tumors showed that the main changes between different tissues are due to subtle changes at the edges of sites that control gene expression. The YMGC researchers also found that tissue specific genes frequently have different methylation neon signs than the commonly needed genes suggesting a specific strategy for regulating these genes. In addition to the neon signs in the promoter, it was also discovered that there are also interesting neon signs inside the gene and these same signs are found in different breast cancer cells of different origins suggesting that these are novel regulatory neon signs whose functions require further investigation in the future. Another important area of investigation is about how many genes are regulated in cohesive way together using a newly developed technique that allows the study of how different set of neon signs are organized inside the cell nucleus and its relationship to control of expression of a complex gene society.

The other type of “neon sign” is the modifications of a specific class of protein that bind to DNA called histones. The methylation and histone neon signs represent different strategies for controlling genes since methylation takes more effort and longer time to change. Therefore, histone neon signs are frequently employed for a strategy to deal with special situations that need to be dealt with quickly. Prof. M.-T. Hsu said there is a newly discovered histone neon sign that specifically marks aggressive cancer cells and is involved in regulating stem cell genes. Understanding of the controlling function of this novel neon sign could shed light on cancer metastasis and stem cell maintenance.

chimpanzee [n.] 黑猩猩
epigenetic [a.] 大量的
sophisticated [a.] 精通的
methylation [n.] 甲基化作用
YMGC [n.] 榮陽基因體研究中心