Researchers at the Sidney Kimmel Cancer Center – Jefferson Health have identified a link between one of the most commonly mutated genes in kidney cancer and the cancer suppressive tumor protein 53 (tp53).
The p53 gene codes for tp53, which regulates the cell cycle and acts as a tumor suppressor through three key functions: Growth arrest, DNA repair, and cell death. If mutations occur in the DNA, tp53 determines whether the DNA can be repaired. If DNA repair is not possible, tp53 triggers cell death.
Mutations in the p53 gene result in defective tp53 proteins and affect the ability of the protein to suppress the formation of tumors. If the DNA is not repaired and cell death is not triggered, the cells proliferate and form tumors. tp53 protein mutants are found in at least 50% of human tumors, but kidney cancers have few tp53 mutations. The p53 pathway was therefore not thought to be particularly relevant in kidney cancer.
The PBRM1 gene is the most commonly mutated gene in kidney cancer. The researchers studied PBRM1 in kidney tumor samples from mice and humans to see whether it serves as a reader of tp53.
Previous research has shown that tp53 acetylation is essential for the activation of tp53’s tumor suppressive functions. The researchers found that the bromodomain 4 (BD4) of PBRM1 binds to the activated tp53 protein but does not bind to its inactive form.
Binding translates the p53 gene’s instructions for tumor suppression. If any mutations occur in PBRM1 BD4 that prevent binding with a specific acetyl group of tp53, the tumor suppressing instructions are not fully read. PBRM1 mutations are found in around 40% of clear cell Renal Cell Carcinomas, the most common subset of kidney cancers.
“This [research] shows us that even though p53 isn’t directly mutated in many kidney cancers, the cancer is still disrupting [the] p53 pathway to drive cancer initiation and growth. This suggests that there might be a therapeutic window for drugs that activate the p53 pathway, which may preferentially impact PBRM1-defective kidney tumors while sparing normal tissues,” says Dr. Yang.
The researchers are now conducting further research to identify drugs that could activate the p53 pathway in patients who have PBRM1 mutations. Since PBRM1 mutations occur in other cancers, the findings could well be applicable to other cancers that do not involve p53 mutations.
You can read more about the study in the paper – PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth – was recently published in the journal Nature Communications. DOI: 10.1038/s41467-019-13608-1