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SPOTLIGHTS
Fumarase: A Novel Molecular Target in Cancer Treatment
On 3rd August 2015, Nature Cell Biology published the article ‘Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.’ Our editor, Yuhui N. Lin took a special interest of the research article and interviewed the corresponding author Prof. Dr. Zhimin Lu from The University of Texas MD Anderson Cancer Center, United States. This coverage includes the concept of DNA repair, the role of fumarase in cancer, cancer research, and Dr Lu’s research laboratory.
 
Dr. Lu is a Ruby E. Rutherford Distinguished Professor of neuro-oncology and molecular and cellular oncology at The University of Texas MD Anderson Cancer Center. He is a member of the editorial boards of more than 10 journals, including Cell Research, the Journal of Biological Chemistry, and Neuro-Oncology. He received the Peter Steck Memorial Young Investigator Award in 2008, Faculty Scholar Award in 2011, Chang Jiang Scholar in 2012, and Potu N. Rao Award for Excellence in Basic Science in 2013. He earned his M.D. in China in 1986 and Ph.D. at The City University of New York in 2008 and completed his postdoctoral training in Dr. Tony Hunter’s laboratory at the Salk Institute for Biological Studies in 2003.

Dr. Lu’s work is aimed at delineating the mechanisms of cellular signaling regulation in cancer cell metabolism, proliferation, migration, and metastasis. His work on integrated regulation of cancer metabolism, gene expression, and cell cycle progression and critical non-metabolic functions of metabolic enzymes in cancer development have made a great contribution to cancer research. Dr. Lu has published many research articles in top-tier journals, including Nature, Cell, Cancer Cell, Nature Cell Biology, Molecular Cell, Nature Communications, Science Signaling and PNAS.

Q: Your recent publication in Nature Cell Biology suggests fumarase plays a critical role in DNA repair. Is fumarase the key to end our long-standing battle against cancer?

A: Our work identifies fumarase as a novel molecular target for treating cancer. Our work indicates that fumarase inhibition will sensitize cancer cells to radiation therapy.

Q: There has been a saying that too much of something can bring harm, and too little may not suffice survival. Is this applicable to fumarate and fumarase? And how is this so?

A: One can think of fumarate and fumarase as having positive or negative effects depending on the cell type. In normal cells, fumarate and fumarase should prevent DNA double strand break-induced apoptosis and decrease the risk of onset of cancer. In contrast, in cancer cells, fumarate and fumarase make cells resistant to radiation therapy.

Q: There are many mutation-types that are known to increase the risk for and to result to the onset of cancer. What makes double-strand DNA (dsDNA) break regions more of a topic of interest? And what are the conditions that could lead to an increased risk for dsDNA break, e.g. environmental or occupational hazard?

A: DNA double strand breaks (DSBs) play a critical role in carcinogenesis. Various types of radiation exposure, including environmental, medical, and occupational radiation exposures, can cause DSBs. Ionizing radiation can induce most, but not all, cancer types, and all kinds of ionizing radiation can cause cancer and other negative health effects. Gamma rays, X-rays, and the higher ultraviolet part of the electromagnetic spectrum are ionizing. In space, natural thermal radiation emissions from matter at extremely high temperatures, such as plasma discharges or the corona of the Sun, may be ionizing.

Q: We live once in our lives, and we will have to die of one disease, eventually. If it is not Cancer or death-by-accident, which is the most likely cause of death? And what are the possibilities for regenerative medicine to play a role in?

A: Cardiovascular disease. Regenerative medicine technologies are being developed to repair and replace damaged heart tissues and revascularize heart tissue in and around areas of infarct. Current areas of study include use of single or mixed populations of cells, both autologous (self to self) and allogeneic (other to self), to reduce or reverse the effects of cardiovascular disease. Development of advanced biologics, gene therapies, and small molecule approaches that focus on the cell cycle or other pathways may allow the regeneration of lost heart cells and tissue.

Q: There is a school of thought whom believes that cancer cells are cells which have lost their ability to senescent, i.e. immortal and continue to divide. And hence, it is considered as a protective mechanism against senescence. What are your opinions about the aforementioned view?

A: I agree in principle with this opinion.

Q: Tell us a bit more about your laboratory (e.g. PhDs, Post-doctorates) and the groundbreaking research you consider to have achieved, and other achievements you would like to obtain in the near future.

A: My laboratory has a team of postdoctoral fellows and PhD students who have a passion for science and research and have been very creative. Our work reveled that metabolic enzymes such as fumarase and pyruvate kinase M2 (PKM2) can possess non-metabolic function critical for tumor development. We have elucidated fundamental mechanisms underlying the Warburg effect. My group for the first time reported that activation of receptor tyrosine kinases induces translocation of PKM2 into the nucleus, where it binds to and activates tyrosine-phosphorylated β-catenin (Nature, 2011). This finding shows that β-catenin is regulated in distinct ways by receptor tyrosine kinases and Wnt ligands. Importantly, transcription factor-associated PKM2 binds to histone H3 and removes HDAC3 from gene promoter regions, leading to subsequent H3 acetylation, gene transcription, and cell cycle progression (Cell, 2012). Nuclear PKM2 promotes the Warburg effect via a positive feedback mechanism by upregulating Glut1, LDHA, and PKM2 expression (Nature Cell Biology, 2012). We continue to study how tumor cells coordinately regulate glycolysis and mitochondrial metabolism and how tumor cells differentially alter the functions of metabolic enzymes and use energy resources, including sugars, lipids, and metabolites, to promote their own growth and proliferation.

Q: As a MD-PhD graduate, could you please illustrate the difference in demands and aspects of being a physician and a clinical researcher?

A: A physician is required to provide the best possible medical care to directly help patients and attempt to cure the patients' diseases. A clinical researcher seeks the answers to unanswered clinical questions in an attempt to find new or better cures of diseases. As an MD-PhD graduate, I have benefited from my knowledge of both basic and medical sciences and my skill in using cutting-edge life science technologies to address fundamental questions in oncology.

Q: Strong collaborative ties are important for ongoing and future research work, would you be keen to move to Asia as a visiting or a distinguished scientist exchange-basis? What are the research areas that you would like to work on?

A: Yes, I would embrace opportunities to partner with colleagues in Asia to work on cancer research.

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