How FH Deficiency Builds Tumor Vulnerabilities

Ever wondered how certain tumors become resistant to treatments? Well, let's dive into the fascinating world of FH deficiency and chromatin helicase CHD6. When a protein called FH is missing or not working right, it leads to a specific type of renal cell carcinoma (RCC). This kind of cancer doesn't respond well to current therapies, making it tough to treat. Researchers have been hunting for new drug targets using a special toolbox of single-guide RNAs. They found that CHD6, a protein that interacts with DNA, is crucial for the growth of these tumors. Without FH, a chemical called fumarate builds up and sticks to another protein, KEAP1, making it useless. This sets off a chain reaction that protects CHD6 from being broken down.With CHD6 now stable, it teams up with another protein, p65, to set up enhancers that trigger inflammation. These enhancers help control how genes are read, influencing what proteins are made. CHD6 also calls in reinforcements, like mSWI/SNF ATPases, to keep the chromatin (DNA and proteins that package our genetic material) open and accessible. Interestingly, a drug called AU-15330 can target and break down the reinforcements, shutting off the enhancers and slowing down the tumor growth in FH-mutated RCC. This drug doesn't mess with the tumors that have working FH. So, CHD6 acts like a bridge, connecting FH deficiency to the assembly of enhancers and making these tumors susceptible to specific epigenetic vulnerabilities.