Abstract

A ChIP-seq analysis of the DNA-binding properties of mutant gain-of-function p53 protein compared to wild-type p53 reveals the gain-of-function proteins bind to and activate a distinct set of genes including chromatin modifying enzymes such as the histone methyltransferase MLL; small molecular inhibitors of MLL function may represent a new target for cancers with mutant p53. Wild-type p53 is a tumour suppressor, but mutation of p53 can promote cancer and certain oncogenic forms are gain-of-function (GOF) mutants. Shelley Berger and colleagues compare the genomic binding patterns of wild- type and gain-of-function mutant p53 using ChIP-seq analysis and find that the p53 mutants bind distinct sets of genes compared to the wild-type protein, with key targets including the histone methyltransferases MLL1 and MLL2, as well as other chromatin modifying enzymes. Gain-of-function p53 mutant cells are highly dependent on the MLL pathway for growth and are sensitive to small molecule inhibitors of MLL function, indicating a novel therapeutic avenue for cancers with these p53 mutations. TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a ‘gain-of-function’ (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.