Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

Li Ren Kong,Chwee Ming Lim,Nur Afiqah Binte Mohamed Salleh,Thi Bich Uyen Le,Chandra Verma ,Lingzhi Wang,Jane Chan ,Mi-Young Lee ,Ashok R Venkitaraman ,David P Lane,Richard Ong ,Srinivasaraghavan Kannan,Giridharan Periyasamy,Hung Huynh ,Tuan Zea Tan,Matan Thangavelu Thangavelu ,Wee Joo Chng,Chit Fang Cheok,Jieying Amelia Lau,Lie Yong Judice Koh,Boon Cher Goh

doi:10.1038/s41467-020-15608-y

Abstract

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.

Highlights

Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation
Among the TP53 mutations found in ~50% of non-small cell lung cancer[24], p53R158G/H/L is one of the most common mutation hotspots according to multiple public databases (TCGA, COSMICS, IARC p53 Database), despite being reported in different frequencies[25]
H2170 LUSC cells that are homozygous for p53R158G (Supplementary Fig. 1B) demonstrated impaired MDM2 and CDKN1A transactivation when treated with Nutlin3a, a MDM2 antagonist, as compared to MRC5 (p53wt) cells, indicating loss of p53 function (Supplementary Fig. 1I)

Summary

Introduction

Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. 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), 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 mutp[53] cells, our work provides a therapeutic opportunity specific to Arg158-mutp[53] tumors utilizing a regimen consisting of DNA-damaging agents and mutp[53] acetylators, which is currently being pursued clinically. We further show in a high-throughput screen that acetylation of p53R158G can be achieved with several pharmacologic agents, providing a cogent basis for further clinical development

Methods

Results

Conclusion