Understanding the process of cancer development is critical for designing effective, personalized cancer treatments. For years, researchers have known that cancer begins with certain types of genetic mutations. One type of cancer gene is called a “tumor suppressor gene.” When working properly, tumor suppressor genes stop malignant cells from undergoing uncontrolled cell proliferation and initiate a process of cell elimination called apoptosis, a form of cell death. Mutations in tumor suppressor genes can cause these genes to lose function, ultimately leading to the development of cancer.
In a study recently published in Cell Reports, researchers at the University of Colorado Anschutz School of Medicine describe the discovery and characterization of a novel protein involved in the mechanism of suppression of different types of tumors.
The tumor suppressor gene known as TP53, which effectively limits the development and growth of many different types of tumors in the body, is the most frequently mutated tumor suppressor gene in human cancers. This gene encodes a protein called p53, which is both a potent inhibitor of cell proliferation and an inducer of apoptosis.
Dr. Zdenek Andrysik, assistant research professor of pharmacology at the University of Colorado School of Medicine and co-author of the paper, said: “In more than half of all cancer cases, TP53 is not mutated, but lies dormant. As a result, much research effort has been devoted to develop drugs to reactivate this latent form of p53 for cancer therapy. However, most cancers respond to p53 activation and these drugs cause a transient block in cell proliferation. A better response to these drugs is the elimination of cancer cells through apoptosis. Therefore, it is crucial for us to understand what other factors are required for effective p53-targeted cancer therapy.”
To address this knowledge gap, Maria Szwarc, Ph.D., and Anna Guarnieri, Ph.D., former pharmacology postdoctoral fellow and co-lead author on the paper, took a multidisciplinary experimental approach, including genetic screening using CRISPR technology to individually disrupt all genes in the human genome and identify which genes require p53 to be fully activated. As a result, the screen identified a protein called FAM193A that is a potent and broad positive regulator of p53 activity, which is poorly understood.
“Our follow-up studies showed that FAM193A is required for the stabilization of the p53 protein and its function,” explains Dr. Szwarc. “It turns out that FAM193A interferes with cytokines that normally inhibit p53 function, the MDM2 and MDM4 proteins, which are often overactive in cancer. We found that FAM193A can antagonize the MDM4 protein, which unleashes p53’s ability to prevent cancer cell proliferation and survival. Consistent with these findings, we document that high levels of FAM193A found in certain tumor types are associated with better prognosis in cancer patients.”
“When we found FAM193A to be a partner of p53 in a genetic screen, there was little question about its function,” said Joaquin Espinosa, Ph.D., “There is little, if any, information available. However, advanced computational analyzes of large-scale datasets of hundreds of cancer cell types and human tumors have revealed a clear functional link between p53 and FAM193A. These findings bring us one step closer to effective p53-based cancer therapy, and FAM193A should be considered. Future research will focus on finding ways to enhance the activity of these partner factors to effectively suppress tumors.”