August 09, 2021
By Richard Saltus
Cancers often stem from mutations in the DNA of cells — changes in genes that normally control cell growth, leading to rogue cell division that forms tumors. But cancer can also be triggered by malfunctions that don't alter the DNA code in cells, but instead disrupt a critical control system that determines which genes are turned on and off across our nearly two meters of DNA packaged in each cell. In fact, about 20% of cancers have breakdowns in what's called the chromatin regulatory system, according to Cigall Kadoch, PhD, a Dana-Farber researcher who is pushing the frontiers of understanding this system, whose importance has been increasingly recognized in cancer and other disorders.
Chromatin refers to a combination of DNA and proteins that folds and packages the DNA in every cell. Chromatin must be "remodeled" — opened and closed at exactly the right time and in the right tissues of the body — to allow genetic instructions in the DNA molecule to be read by the cell's protein-making machinery. This opening and closing is carried out by chromatin remodeling complexes — modular components inside the nucleus of cells made up of dozens of proteins. Different chromatin remodeling complexes work in tandem with transcription factors, which help direct the remodeling complexes to the right locations on chromatin.
Watch the short animation below to see how chromatin opens so that genes in the DNA strand can be expressed.
Understanding the Chromatin Regulatory Complex
The Chromatin Regulatory Complex is made up of numerous proteins organized into functional modules. Mutations in a regulatory complex can cause "wrong" genes to be expressed, causing cancer or other diseases.
When there is a glitch in a remodeling complex — for instance, when a mutation alters one of the proteins in the complex or there is too much of a transcription factor that interacts with it — the complex can malfunction, leading to overactivation of cell growth-promoting genes or inactivation of genes that normally keep growth under control. The result can be the transformation of a normal cell into a cancer cell, and runaway growth leading to tumors.
Kadoch and her laboratory team are investigating a particular chromatin remodeler called mSWI/SNF, made up of 29 proteins, which interacts with more than 100 different transcription partners to activate certain genes. The mSWI/SNF complex is strongly implicated in abnormal gene expression leading to disease owing to its high frequency of mutations in its component proteins.
As they dissect the intricate workings of the chromatin remodeling complexes, Kadoch and her affiliates are pursuing clever strategies to target misbehaving mSWI/SNF remodelers in cancer. One tactic is to directly inhibit the activity of specific remodeler proteins in the complex, which is currently being tested for the first time in patients in clinical trials targeting both leukemia and melanoma. Another plan is to use drugs called protein degraders to eliminate certain proteins in the mSWI/SNF complex, leading to cancer cell death, a second type of strategy on the precipice of clinical evaluation. And a third strategy is to interrupt the interaction between parts of the mSWI/SNF complex and transcription factors that are over-activating cancer-causing genes.
