Mutant genes can drive cancer, but so can normal genes when they are turned on at the wrong time in the wrong tissues of the body because of malfunctioning genetic control mechanisms.
The laboratory of Dana-Farber’s Cigall Kadoch, PhD, has a laser-like focus on one such control unit: a cluster of proteins called the BAF complex. BAF complexes, when mutated or misbehaving, are being linked to a growing list of cancers (over 20 percent in total), ranging from several rare pediatric sarcomas to more common cancers such as lung cancers.
Most recently, Kadoch and her team have implicated BAF complexes in prostate cancer, the second leading cause of cancer death in American men.
The discovery of BAF’s role in prostate cancer suggests potential new targeted therapeutic strategies for this disease, say Kadoch and colleagues at Dana-Farber and the Broad Institute of MIT and Harvard, who published their findings in Molecular Cell.
BAF complexes, which are termed “chromatin remodeling complexes,” help coordinate gene expression programs within the cell by binding to different sections of chromatin—the structure that packages the nearly two meters of DNA carrying our genetic code in each cell. When BAF complexes bind chromatin, they expose the appropriate genes to the cell’s transcriptional machinery that turns genes’ instructions into functioning proteins.
BAF complexes can acts as an accomplice in cancer when they are “hijacked” and abnormally target to and turn on genes that should be kept inactive, leading to cancerous growth.
Identifying the Link to Prostate Cancer
The Kadoch group has identified hijacking of BAF complexes as a key step in the development of prostate cancer, specifically prostate cancer cells containing an overactive transcription factor called ERG. ERG belongs to a family of transcription factors that regulate the expression of an array of different genes in various tissue types.
ERG is normally silent and “should not be expressed in the prostate,” notes Kadoch. But more than a decade ago, it was found that ERG is highly expressed in more than half of prostate cancers. This is the result of a chromosomal accident that fuses ERG with another gene, TMPRSS2, which turns on ERG expression at very high levels.
The big unanswered question, though, was how ERG’s overactive presence in prostate cells caused them to become cancerous.
Now, Kadoch and her colleagues have discovered the answer. They found that ERG binds to the surface of BAF chromatin regulatory complexes and commandeers them, sending them to destinations in the cell’s genome where they turn on target genes that drive the cells into a malignant state. Further confirmation of BAF’s key role was that BAF was found necessary for cancer-promoting gene expression in ERG-driven prostate cells and for organoid models to make a transition from the basal state to the luminal state— a hallmark step in cancer development.
The researchers’ discovery that ERG binds to the surface of the BAF protein complex “is the really exciting part,” says Kadoch. That’s because the ERG-BAF binding interaction is weak, and therefore potentially could be broken by a designer drug, interrupting development of prostate cancer, she says. In fact, she adds, a patent on the discovery has already been licensed to a pharmaceutical company.
Kadoch expects there will be more discoveries of how transcription factors like ERG commandeer BAF and other chromatin regulatory complexes to initiate cancer and other diseases. “I think it’s the dawn of a new era in thinking about mechanisms of transcription,” she says.
First authors on the study in Molecular Cell are Gabriel J. Sandoval, PhD, and John L. Pulice. Senior and corresponding authors are Kadoch and William Hahn, MD, PhD.
This article was originally published on August 23, 2018, by Dana-Farber Cancer Institute. It is republished with permission.