According to the study published today in the Proceedings of the National Academy of Sciences USA, YY1 regulates p53 at multiple levels. First, YY1 uses the novel mechanism of causing Mdm2, a key oncogene that marks proteins for degradation, to have an enhanced interaction with p53. This results in a decrease in the amount of p53 in the cell. YY1 also directly blocks p53's interaction with its cofactors, such that p53 can no longer act as a transcription factor to cause cell suicide in response to DNA damage.
"In terms of possible therapies for the future, YY1's regulation of p53 at different levels means that we have new, different targeting options," says LICR's Dr. Johan Ericsson, the senior author of the study. "We know that we can use small molecules to prevent transcription factors from interacting with other proteins, so we can consider blocking YY1's direct interaction with p53 as a therapy option. We can also think about ways of disrupting the Mdm2 and YY1 interaction, and so prevent the indirect inhibition of p53."
For now, Ericsson and his team are focused on investigating the growing body of evidence that suggests YY1 could be a pivotal transcription factor in cancer. "YY1 interacts with several transcription factors involved in cancer, for example, Myc and Notch, and now
Contact: Sarah L. White, Ph.D.
Ludwig Institute for Cancer Research