Targeting p53 through modulation of USP7 is a potential therapeutic strategy for cancer


p53 is a well-studied tumor suppressor gene. Because of its near universal alteration in cancer, p53 has long been identified as a therapeutic target for cancer. However, extensive research suggested that p53 is extremely difficult to hit.

Now, scientists have found a promising way to target this "undruggable" protein. Findings of the study were summarized in a paper appearing online in Nature on 18 October 2017. The study was conducted by several research institutes in the UK and the USA. Andrew Turnbull and Wojciech Krajewski from London Bioscience Innovation Centre, and Stephanos Ioannidis from FORMA Therapeutics are the co-first authors.

Since the p53 protein is hard to hit, the researchers put their eyes on an essential mechanism that controls intracellular protein degradation and turnover, the ubiquitin-proteasome system. One player involved in this system is the enzyme USP7 (or called HAUSP). USP7 is a deubiquitylating enzyme. It removes ubiquitin from target proteins such as p53, thus protecting target proteins from degradation. This process is called deubiquitination.

Turnbull and colleagues found that two compounds, FT671 and FT827, were able to selectively bind to a specific region in USP7, and this interaction resulted in increased p53 levels, the transcription of p53 target genes, and the inhibition of tumor growth in vivo. Taken together, these data show the possibility of targeting the "undruggable" p53 protein by modulating USP7 or other deubiquitylating enzymes.

According to Benedikt Kessler, one of the study's corresponding authors and a professor of biochemistry and mass spectrometry at the University of Oxford, the study would have implications in the treatment of cancer, immunological diseases, neurodegenerative diseases, and other chronic diseases.

The deubiquitylating enzyme family has diverse physiological roles, but the underlying mechanisms are still poorly understood. Prof. Kessler intends to analyze the roles of the deubiquitylating enzyme family in the context of host-pathogen interactions and tumourigenesis.
 
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