Mutations in p53 cause cancer cell growth by upregulating chromatin-modifying enzymes.

TP53, the gene encoding p53, is the most commonly mutated gene in human cancers. While many mutations destroy the tumor-suppressing activity of p53, some pack an added punch: So-called gain-of-function (GOF) mutations give rise to proteins with additional oncogenic properties that cause more aggressive tumors, and contribute to drug resistance.

A new study suggests that GOF p53 mutants gain their potency by targeting cellular pathways regulating chromatin structure. The work reveals a link between p53 and epigenetic changes, which regulate gene expression and are a popular target for new cancer therapies.

In its normal form, p53 binds to DNA to regulate gene expression and control cell growth. In the study, the researchers found that GOF p53 mutants bind to different locations on DNA than wild-type p53, suggesting that the mutants regulate a distinct set of genes. One prominent pathway featured histone-modifying enzymes, regulators that alter chromatin structure and globally activate gene expression. In cells, GOF p53 expression upregulated expression of two key histone methyltransferases, MLL1 and MLL2, as well as the acetyltransferase MOZ, and led to genome-wide increases in histone methylation and acetylation.

The GOF effect was also apparent in patient-derived tumor samples. Using expression data from The Cancer Genome Atlas, the researchers found a correlation between GOF p53 mutations and higher mRNA of MLL1, MLL2, and MOZ. Expression of the genes was not significantly increased in tumors with wild-type p53, or tumors lacking p53.

MLL1 was critical to the ability of GOF p53 to cause cell proliferation, the researchers showed. Genetic knockdown or pharmacological inhibition of MLL1 protein function decreased the growth of GOF p53–expressing tumor cells, but not p53-null cells.

The results suggest that the MLL1 protein might provide a therapeutic target for a wide range of tumor types with GOF p53 mutations. “The MLL1 gene is often altered in leukemia, but in solid cancers, MLL1 was not seen to be a major target,” says study leader Shelley L. Berger, PhD, from the University of Pennsylvania in Philadelphia. “We're really excited that solid tumors with p53 gain-of-function mutations could also be treatable with MLL1 inhibitors.”

The findings “could explain why so many genes are affected by the presence of gain-of-function p53,” write Carol Prives, PhD, of Columbia University, and Scott W. Lowe, PhD, of the Memorial Sloan Kettering Cancer Center, both in New York, NY, in an accompanying commentary. Although more work will be needed to establish the specificity and toxicity of MLL inhibition, this study “might point to treatments for tumors that harbor TP53 mutations,” they write.