Santiago Ropero and Manel Esteller worked together in the epigenetics laboratory of the National Cancer Research Center (Centro Nacional de Investigaciones Oncológicas) (CNIO) when they published in Nature Genetics in 2006 the discovery of the mutation in an epigenetic gene in human cancer. Three years later, Ropero, from the department of biochemistry and molecular biology at the University of Alcalá de Henares, and Esteller, as program director of epigenetics and cancer biology at the Bellvitge Biomedical Research Institute (Institut d’Investigació Biomèdica de Bellvitge) (IDIBELL) met again in Barcelona to receive the eleventh Esteve Foundation Research Award for that article in which they described the alteration of the HDAC2 gene, present in 25% of tumors of the colon, stomach and uterus of a special subtype.
The members of the jury that decided the recipient of the award, made up of pharmacologists John Wood (London), Sergio Erill (Barcelona), Patrick du Souich (Montreal), considered the article, out of all those that were entered for the prize, to be the best research in the field of pharmacology published by a Spanish author in an international journal during 2006 and 2007. The prize, awarded every two years and worth 18,000 euros, was presented on June 30 at the IDIBELL headquarters in Duran and Reynals Hospital, L’Hospitalet de Llobregat, in the presence of its director general, Dr.Emilià Pola, and the director of the Esteve Foundation, Dr. Felix Bosch, together with the award-winning authors.
What does it mean to discover for the first time the epigenetic gene mutation in human cancer?
Manel Esteller (ME): What this mutation does is open a new avenue by which human tumors appear. Until now, we knew that human tumors appeared by mutation in genes involved in cell signaling or by mutations in membrane receptors, for example. Also by alterations in hormone receptors, but we didn’t know that the mechanism that regulates gene expression, which consists of the epigenetic genes, was involved. Thus, a new avenue for the formation of tumors was found, which enables the design of new drugs designed to repair or block that path.
Specifically, what are the implications of altering the HDAC2 gene described in the award-winning work?
ME: The histone deacetylase number 2, which is what we have found mutated in human tumors, is a gene whose function is that of a controller in the repression of genes. It ensures that genes are expressed only where they have to express themselves. Therefore, this mutation provokes the creation of an aberrant expression, one which hundreds of genes express in a form they shouldn’t and are then converted into genes with oncogenic activity. Consequently, if we think of ways to recuperate the activity of this deacetylase, we could find potential antitumor therapies.
What consequences have your scientific findings had now that it has been three years since the publication of the article?
ME: This publication opened our eyes at the time of looking for gene mutations in new cancer pathways. Recently, we also published in Nature Genetics on a mutation in another distinct pathway linked to cancer, which is a mutation in the production pathway of microRNAs, small molecules of ribonucleic acid (RNA) that act as interrupters of gene expression. This mutation has been discovered, in part, thanks to the results of the first article.
Are there many other mutations in epigenetic genes that, above all else, contribute to the development of cancer?
ME: Since that year, 2006, alterations in other epigenetic genes have been discovered, which are mostly gene amplifications, transmutations, typically present in leukemias, lymphomas and in some solid tumors, such as prostate cancer.
Why is it so difficult to define the concept of epigenetics?
ME: Epigenetics is an old discipline, in the sense that there has always been an intuition that the enviroment left some chemical fingerprints in human beings, in their make-up. But it wasn’t until the early 1990’s that there really was a technical advance that allowed the study of epigenetics from a more abstract view to a more practical one.
If you had to describe epigenetics to someone unaware of its existence, how would you do it?
ME: Epigenetics is the regulatory agent of the genome, which regulates our DNA. If DNA is the ‘hardware’ of your computer (screen, hard drive, etc.), epigenetics is the ‘software’, all the programs we produce (some allow us to draw, others to send an email, etc. ). Epigenetics, therefore, is the ‘software’ that enables us to operate the machine that is our genetic material.
To what extent does epigenetics depend on us, on our lifestyle?
ME: It is clear that many things we do leave marks on our cells. Some are long lasting and others more short-term, lasting minutes, hours or days. But some may take years or even be passed on to the next generation. For example, there are memory mechanisms, such as the fact that a smell can bring back childhood memories of 40 years ago. The first mechanism left a mark on our genetic material, on our DNA. This is an example of epigenetic marks.
Can modifying our less healthy habits, such as smoking or excessive exposure to sun, improve our epigenetics?
ME: In the case of tobacco, we know that a person who quits smoking, after a few years acquires a similar risk as a nonsmoker, and there is thus a reversible mechanism. Therefore, our habits can change our epigenetics and, consequently, the activity of our genes.
Why are so many researchers working in fields such as genetics or cellular biology turning to epigenetics?
Santiago Ropero (SR): The fact that they have come to do research in epigenetics is because it is a new field. Until about ten or was twelve years ago it was virtually unknown. Gradually, researchers working in cellular biology have realized that epigenetics is an indispensable tool for their studies. When they begin to realize why many genes are changing their expression or why they change cellular functions, they need to look to epigenetics. Epigenetics is a new discipline, but it was virtually unknown a few years ago. Although we still have much to learn, this is a very useful tool.
How would Santiago Ropero define epigenetics?
SR: There are many ways to define epigenetics. One of them is that epigenetics studies how gene expression is regulated. It studies all the changes that occur in the DNA environment and which cause changes in gene expression.
How goes the search for the epigenome?
ME: The epigenome is an ambitious project. If each individual has a genome, they also have about 150 epigenomes, one for each cell type, so it is an expensive project. Still, we already have ideas of simple cell epigenomes, such as lymphocytes or fibroblasts, and also of altered cells in certain types of tumors such as leukemias. We ourselves have recently finished work on epigenomes of viruses that cause infectious diseases and tumors, which are viruses with double-stranded DNA that act like the human genome. It is a small project that has provided the springboard for later human epigenomes.
What work does the Program for Epigenetics and Cancer Biology (PECB) of the Institute of Biomedical Research of Bellvitge (IDIBELL) actually do?
ME: The program is working at understanding the epigenetic causes of cancer, in the development of epigenetic biomarkers of disease, in both prognosis and explanation, and finally in the preclinical stage of molecules that act as potential antitumor agents at the epigenetic level.
One year later, how does Manel Esteller consider his move from CNIO to IDIBELL?
ME: In my opinon, very good. There are more responsibilities, but in this sense it is always an adventure. On the other hand, it also means coming back home …
Finally, what does it mean to the team to be awarded the Eleventh Esteve Foundation Research Award?
SR: Very positive. Whenever one is recognized for a work of this type, nationally as much as internationally, it is very satisfying for us. It is satisfying in itself when you achieve some results, as in this case the first discovery of a mutation of the HDAC2 gene, but even more so when institutions such as the Esteve Foundation recognize the work.
The title of the article was A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. It was the first to describe mutation of the HDAC2 gene, pivotal in the regulation of many other genes, such that its inactivation facilitates the generation of other alterations in oncogenes and genes that suppress tumors. The findings of these researchers could be useful for predicting which tumors will be more sensitive to tomorrow’s drugs used in chemotherapy of cancer, called histone deacetylase inhibitors.