MYC is a protein that has a crucial role in virtually all types of cancer, but developing safe and efficient drugs to target MYC in patients has proven very difficult. Now researchers have discovered a new function of MYC, which potentially provides new ways of targeting the progression of cancer.
MYC is an important protein for most cells in the human body because it controls many aspects of the biology of the cell, including cell division and the metabolism of nutrients. MYC also has a very important role as a transcription factor in most types of cancer.
Cancer cells grow rapidly, and this is facilitated by increasing the level of MYC protein in the cells, which promotes cell division.
Now researchers have identified a new function of MYC in cancer, and this function can become a highly relevant target in developing new treatments for many types of cancer, including breast cancer, lung cancer, prostate cancer and colorectal cancer.
“MYC is the holy grail in cancer treatment, because a drug that targets MYC could potentially treat people with many types of cancer. Targeting MYC directly has proven very difficult, but we have found a new function that could be a potential target for future treatments. This new function depends on other specific helper proteins, and if we can target these, we can probably suppress this function of MYC and thus inhibit the growth of cancer cells,” explains Rasmus Siersbæk, a researcher involved in the study and Associate Professor at the Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.
The research has been published in Nature Genetics.
MYC regulates gene expression
MYC is a transcription factor that binds to DNA and helps to switch various genes on or off.
The DNA of each human cell contains about 25,000 genes, but only some of them need to be used in a given cell type. The others should preferably be switched off.
MYC works by binding to regions called promoters, located next to our genes in the DNA, where it cooperates with other proteins to turn on gene expression.
Human DNA contains lots of regions like this that are not part of the genes but play important roles in the precise regulation of gene expression, which is critical for proper cell function.
Enhancers represent another type of regulatory region located far away from the genes in our DNA. Despite the large distance separating enhancers from genes, they are nevertheless important for proper regulation of gene expression.
The process works by DNA folding up and forming a loop that brings genes and enhancer regions together. MYC also binds to such enhancers.
“In normal cells, MYC mainly binds to promoters, but MYC also starts to bind to enhancer regions when it is expressed at high levels, such as in cancer cells. But this enhancer binding of MYC in cancer cells has not received much attention,” says Rasmus Siersbæk.
Investigating MYC activity
The researchers aimed to learn more about the significance of MYC also binding to enhancer regions, especially in cancer cells.
They therefore studied how MYC and other proteins bind to DNA by pulling down these proteins from a mixture of proteins and DNA from breast cancer cells and using sequencing analysis to characterise the parts of the DNA to which the proteins bind.
The results revealed several interesting things.
MYC requires assistance from other transcription factors to enable it to bind to enhancer regions. Furthermore, the binding of MYC to enhancer regions helps to regulate other genes than MYC promoter binding.
Thus, MYC can switch on hundreds of genes by binding to promoter regions and hundreds of other genes by binding to enhancer regions.
“We did not know about this function of MYC on enhancers. MYC thus appears to be able to activate another group of genes important for the cancer cells from these regions in our DNA. Since this enhancer function of MYC mainly takes place in cancer cells, we may be able to develop drugs that specifically target this function of MYC and thus preferentially target cancer cells and not healthy cells,” explains Rasmus Siersbæk.
Possibility of inhibiting MYC function
The discovery does not change the fact that developing drugs that can directly bind to and inhibit MYC is still very difficult. Researchers have attempted to do this for many years, but it has not led to new cancer treatments benefitting cancer patients so far.
However, Rasmus Siersbæk sees great potential in moving in a different direction: targeting the helper proteins that MYC requires to activate genes. In fact, the researchers have already carried out experiments in this direction.
They found that MYC activates genes differently from promoters and enhancers by cooperating with different types of helper proteins in these regions.
They identified the helper protein GCN5 as being important for MYC’s ability to activate enhancer regions and the genes they control.
The researchers were able to inhibit GCN5 and thereby reduce the enhancer function of MYC.
“This looks very interesting right now. We are still doing experiments to find the most important helper proteins and investigate how they work. But if we can understand the cellular mechanisms that control the enhancer function of MYC, and if we can find a way to target these mechanisms, we can hopefully create the basis for developing new drugs that can target many different types of cancer,” concludes Rasmus Siersbæk.
