Gain of function p53 mutant R273H confers distinct methylation profiles and consequent YAP/TAZ signaling mediated activation of partial or full EMT states to colon tumours.

BACKGROUND: Mutations in tumour suppressor p53 are frequently implied in aggressive progression and metastasis in colorectal cancer. But the distinct phenotypes exhibited by site-specific mutations of p53 are not well elucidated. Here, we investigate the epigenetic and transcriptional impact of three major p53 hotspot mutations (R175H, R273H and R282W), through DNA methylation changes and single cell transcriptomics.

RESULTS: We observed that the p53 R273H mutation is associated with a partial epithelial-mesenchymal transition (pEMT) and increased metastatic progression. Analysis of DNA methylation patterns revealed a distinct epigenetic landscape in R273H-mutant tumours, with hypomethylated regions correlating with enhanced transcriptional activation of YAP/TAZ target genes thus promoting pEMT and EMT-like phenotype in CRC tumours. In vitro ChIP-seq experiments in colorectal cancer cells expressing the R273H mutant p53 (HT29) showed enrichment of mutant p53 at the promoters of YAP/TAZ target genes suggesting EMT/pEMT like states with R273H mutation. Further, simulations from a gene regulatory network incorporating the interactions of p53R273H with EMT regulators explain how this mutation shapes the phenotypic landscape accessible to cancer cells. Our analysis of single-cell transcriptomes of colorectal tumours reveals R273H-linked enrichment of partial and mesenchymal EMT phenotypes across tumour subpopulations in CRC.

CONCLUSIONS: We identified a distinct epigenetic signature associated with the p53 R273H mutation, characterised by hypomethylation of YAP/TAZ signalling genes that drives partial EMT and aggressive tumour behaviour. These findings highlight the importance of mutation-specific epigenetic regulation in shaping colorectal cancer progression and the need for developing therapeutic strategies tailored to p53 mutation status.