Using a rare, lethal form of ovarian cancer as a lens, scientists at Dana-Farber Cancer Institute have discovered how the loss of two key, enzymatic parts of a gene-regulating protein complex in cells can drive them into malignant growth.
Investigators led by Cigall Kadoch, PhD, found that when two components that serve as the “engines” of the SWI/SNF chromatin remodeling complex are both mutated – as they invariably are in the rare ovarian cancer type known as SCCOHT– genes that are normally expressed in the healthy ovary are shut off, and genes that allow the cell cycle to run unchecked are turned on.
The report, published online in Nature Genetics, is the latest in a series of findings from the Kadoch group that are revealing the impact of mutations in different parts of the SWI/SNF complex, which are found in over 20 percent of cancers and in some intellectual disability disorders. The SWI/SNF complex is a modular structure inside the nucleus of cells made up of many protein subunits; the function of the complex is to remodel the way DNA is packaged, thereby orchestrating the switching on and off of genes so that certain proteins are made at the appropriate times in cells. Mutations in the SWI/SNF complex lead to sets of genes being inappropriately expressed, which can trigger the development of cancer. Kadoch and her team hope to uncover molecular targets for drugs to treat SWI/SNF-associated cancers and other disorders.
“Many new insights in to both basic mechanisms as well as potential therapeutic opportunities have been gained by studying rare cancer types that are uniformly or nearly uniformly driven by problems in this complex, with few to no other recurrent events,” said Kadoch.
In their new research, the investigators focused on SCCOHT (small cell carcinoma of the ovary, hypercalcemic type), an extremely rare but devastating form of ovarian cancer with a two-year survival rate of less than 35 percent. The median age at diagnosis is 24 for this aggressive cancer, which can even develop in girls under two years of age.
The cancer has been linked to mutations in two genes – SMARCA2 and SMARCA4 – that code for the two proteins in the SWI/SNF chromatin remodeling complex that give it its energy, termed ATPases. These ATPases process energy in the form of ATP to move the SWI/SNF complex along the genome. How cancer develops from the loss of these two subunits wasn’t known, which prompted Kadoch and her colleagues to investigate.
“We sought to detail the precise biochemical and functional consequences of loss of the SMARCA4 and SMARCA2 proteins, also called BRG1 and BRM, in SCCOHT cell lines,” Kadoch explains. The researchers found that these proteins as well as several other protein components assemble together on to SWI/SNF complexes in an “ATPase module.”
“Without the ATPase module, the residual components of the SWI/SNF complex do bind chromatin but non-specifically, and without function, preventing activation of normal ovarian genes” said Kadoch.
“Importantly, we found that the ATPase module is critical for the proper specification of different types of SWI/SNF complexes and hence acts as a tumor suppressor in these ovarian cells,” Kadoch explained. “In the absence of the ATPase module, cell cycle genes are upregulated, and the cells divide rapidly. However, when we restored the ATPase module in SCCOHT ovarian cancer cells, SWI/SNF complex activity was restored and genes required for proper cell differentiation were reactivated, halting cell proliferation.”
The researchers note that the findings reflect another example of how studying rare cancers can reveal mechanisms that are relevant to many cancers. They hope to follow up on these results to develop therapeutic strategies for this specific group of patients.
First author of the paper is Joshua Pan, a graduate student in the Kadoch group.
The research was supported by funding from the National Science Foundation Graduate Research Fellowship No. 2015185722 and NIH T32 Training Grant in Genetics and Genomics; the NIH DP2 New Innovator Award No. 1D2CA195762-01; the American Cancer Research Scholar Award No. RSG-14-051-01-DMC and the Pew-Stewart Scholars in Cancer Research Grant.
Kadoch is a scientific founder, fiduciary Board of Directors member, Scientific Advisory Board member, consultant and shareholder of Foghorn Therapeutics, Inc.