SINGAPORE -- Obesity is a well known risk factor for prostate, breast and colon cancer, but recent studies have shown that a protein responsible for generating fat cells also plays an important role in cancer. Researchers at the Genome Institute of Singapore have conducted, for the first time, a genome-wide analysis of how the protein, called perixosome proliferator-activated receptor gamma (PPARg), turns on various genes related to obesity.
Simply suppressing the protein entirely could prevent the generation of adipocytes - the precursors to fat cells - the researchers say, but it would decrease the protein's beneficial properties. Instead, the researchers believe that by identifying the gene targets of PPARg, they could open up new targets for drug development against a number of diseases, including obesity, diabetes and cancer. They present their findings today at the AACR Centennial Conference on Translational Cancer Medicine.
"To date, only a limited number of direct targets for PPARg have been identified. Our findings provide a genome-wide map of PPARg binding sites during the course of adipocyte differentiation," said M. Sabry Hamza, Ph.D, a postdoctoral research fellow at the Genome Institute of Singapore, a division of Singapore's Agency for Science, Technology and Research (A*STAR). "These results together with the expression profile of genes that are dependent of PPARg expression provide us with clues into the transcriptional circuitry during adipogenesis, the process by which adipocytes differentiate into different types of fat tissue."
With funding from A*STAR, "we have identified direct targets of PPARg, that when inhibited lead to a dramatic reduction of adipogenic potential," Hamza said. "Ongoing analysis will help us decipher whether these direct targets control adipogenesis, insulin sensitization or determination of fat cell type."
According to Hamza, PPARg inhibits the proliferation and lowers the threshold for apoptosis -- the process by which cancer cells destroy themselves. "In addition, significant increase in tumor suppressor BRCA1 is induced when breast cancer cells are exposed to PPARg agonists," said Hamza. "Although indirect, the role of PPARg as it relates to obesity and cancer is intriguing."
So far, Hamza and his colleagues have identified a number of new PPARg target genes which are connected to adipogenesis and insulin sensitivity. Currently available marketed oral hypoglycemic drugs, although very potent in treating type II diabetes, cause detrimental sides effects including weight gain, liver toxicity and heart disease, says Hamza. "Using drugs which target specifically those PPARg targets regulating insulin sensitivity could hence present a safer and more efficient therapeutical approach," said Hamza.
According to Hamza, the researchers' next step will be to apply their data to mouse models in order to compare PPARg activity in fat tissue of mice under high-fat and normal conditions and to further characterize the regulation of PPARg target genes identified in this study.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.
The Agency for Science, Technology and Research, or A*STAR, is Singapore's lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based Singapore. A*STAR actively nurtures public sector research and development in Biomedical Sciences, Physical Sciences and Engineering, with a particular focus on fields essential to Singapore's manufacturing industry and new growth industries. It oversees 14 research institutes and supports extramural research with the universities, hospital research centres and other local and international partners. At the heart of this knowledge intensive work is human capital. Top local and international scientific talent drive knowledge creation at A*STAR research institutes. The Agency also sends scholars for undergraduate, graduate and post-doctoral training in the best universities, a reflection of the high priority A*STAR places on nurturing the next generation of scientific talent.
The Genome Institute of Singapore (GIS) is a member of the Agency for Science, Technology and Research (A*STAR). It is a national initiative with a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine. The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.