A new method has been found for identifying therapeutic targets in cancers lacking specific key tumor suppressor genes. The process, which located a genetic site for the most common form of prostate cancer, has potential for developing precision therapy for other cancers, such as breast, brain, and colorectal, say researchers at The University of Texas MD Anderson Cancer Center. Study results appeared February 6 in the journal Nature, in an article entitled, “Synthetic Essentiality of Chromatin Remodelling Factor CHD1 in PTEN-Deficient Cancer.”
By searching for gene deletion patterns in cancer through a concept the investigators call “synthetic essentiality,” the team identified a synthetic-essential gene known as chromatin helicase DNA-binding factor (CHD1) as a therapeutic target for prostate and breast cancers lacking a tumor suppressor gene called phosphatase and tensin homolog (PTEN). Tumor suppressor genes are deleted in many cancers, leading to tumor formation and growth.
The MD Anderson scientists focused on PTEN-deficient prostate and breast cancers. In these cancers, the scientists found, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival, and tumorigenic potential.
“Mechanistically, functional PTEN stimulates the GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the β-TrCP-mediated ubiquitination–proteasome pathway,” wrote the authors of the Nature article. “Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF–NF-κB gene network.”
“We searched for genes that are occasionally deleted in some cancers but which are retained in cancers caused by specific tumor suppressing genes, such as PTEN,” said Di Zhao, Ph.D., Odyssey postdoctoral fellow in cancer biology and first author on the Nature paper. “We reasoned that this retained synthetic essential gene might be required for cancer-promoting actions when the cancers lose specific tumor suppressor genes.”
Prostate cancer often occurs when it deletes PTEN, commonly associated with advanced prostate cancer. The Centers for Disease Control cites prostate cancer as the second leading cause of cancer-related death for men in the U.S., with 176,000 new cases and 28,000 deaths reported annually. Up to 70% of primary prostate tumors are PTEN-deficient.
Through analyzing prostate cancer genome databases from The Cancer Genome Atlas and other sources, the research team found that CHD1, while occasionally deleted in some prostate cancers, was consistently retained in PTEN-deficient prostate cancer. Further investigation uncovered CHD1's role as vital to PTEN signaling, and as a potential therapeutic target in prostate and breast cancers with PTEN gene loss.
“Identifying targets essential to cell survival in tumor suppressor genes has long been an investigational goal with the aim of offering cancer-specific vulnerabilities for targeted therapy,” said Ronald DePinho, M.D., professor of Cancer Biology, MD Anderson president, and senior author for the Nature paper. “This study provided a conceptual framework for the discovery of 'traceable' targets in cancers harboring specific tumor suppressor deficiencies.”
Dr. DePinho added that further analyses are needed to verify additional synthetic essential genes in cancer cells that harbor specific genomic alterations as well as to identify potential regulatory interactions and cell-essential mechanisms.