A Year After Common, Novel SPOP Prostate Cancer Gene Mutation Identified, Researchers Determine Its Route to Cancer
When SPOP is mutated it no longer can act as a tumor suppressor gene
April 03, 2013—Last year, PCF-funded researchers reported in Nature Genetics that some 15 percent of all prostate cancer tumors contain a mutation in a gene known as SPOP. This non-hereditary mutation is the most common acquired single-point mutation found to date in prostate cancer. (Single point mutations occur when one just one nucleotide “letter” of DNA is substituted for another.) At the time, because the SPOP mutation often occurred early in the disease, researchers speculated it might be an important tumor initiator. And because a normally functioning SPOP gene performs essential housekeeping cellular functions, such as determining what molecular tidbits to keep and what to mark for destruction, researchers had an important clue about how a malfunctioning, mutated SPOP gene might contribute to cancer initiation and progression.
Indeed, building on last year’s discovery, other PCF-funded investigators have now published a paper in the Proceedings of the National Academy of Science (PNAS) demonstrating how the SPOP mutation likely spurs prostate cancer development and growth. This step-wise scientific discovery highlights the significance of this master regulator as a theraputic target in prostate cancer.
Dr. Nicholas Mitsiades, of Baylor College of Medicine in Houston, TX and a PCF Young Investigator, is the senior author on the PNAS paper and has long studied master-regulator genes known as SRCs. Overexpression of the SRCs is linked to a number of human cancers, and is associated with increased lethality and development of resistance to anti-cancer therapies. Indeed, the gene SRC-3 acts as an oncogene when levels of its protein are overexpressed. When the housekeeping SPOP gene is not mutated, it acts as a tumor suppressor gene by marking SRC-3 proteins for destruction. However, when a single point mutation occurs in the SPOP gene, it can no longer direct the removal of the SRC-3 protein.
In essence, when too much SRC-3 protein trash piles up in a cell, cells can become cancerous.
Now that a mechanism of action has been found for how mutations in SPOP can cause prostate cancer, the next step is thwart the production of SRC-3 protein say the researchers, writing that SRC-3 is an important drug target. Dr. Bert O'Malley, Professor and Chair of Molecular Biology at Baylor College of Medicine, a co-author on the PNAS paper, is currently working on developing therapeutics to inhibit SRC-3.