Kong, L.R., Ong, R.W., Tan, T.Z. et al. Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation. Nat Commun 11, 2086 (2020). https://doi.org/10.1038/s41467-020-15608-y
Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically.
This work was funded to Boon-Cher Goh by the Singapore Ministry of Health’s National Medical Research Council, the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives. S.K. and C.S.V. thank A*STAR (including an Industry Alignment Pre-Positioning Grant for the Peptide Engineering Program; grant IDs H17/01/a0/010, IAF111213C) and National Supercomputing Centre Singapore for their support.