Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-020-15608-y
Title: Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation
Authors: Kong, Li Ren 
Ong, Richard Weijie
Tan, Tuan Zea 
Salleh, Nur Afiqah Binte Mohamed 
Thangavelu, Matan
Chan, Jane Vin
Koh, Lie Yong Judice
Periyasamy, Giridharan
Lau, Jieying Amelia 
Le, Thi Bich Uyen
Wang, Lingzhi 
Lee, Miyoung
Kannan, Srinivasaraghavan
Verma, Chandra S 
Lim, Chwee Ming 
Chng, Wee Joo 
Lane, David P 
Venkitaraman, Ashok 
Hung, Huynh The
Cheok, Chit Fang 
Goh, Boon Cher 
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
NF-KAPPA-B
INTERACTING PROTEIN TRIP
TUMOR-SUPPRESSOR PROTEIN
MUTANT P53
DNA-BINDING
MOUSE MODELS
COMMON GAIN
ACTIVATION
PROMOTES
CELLS
Issue Date: 29-Apr-2020
Publisher: NATURE PUBLISHING GROUP
Citation: Kong, Li Ren, Ong, Richard Weijie, Tan, Tuan Zea, Salleh, Nur Afiqah Binte Mohamed, Thangavelu, Matan, Chan, Jane Vin, Koh, Lie Yong Judice, Periyasamy, Giridharan, Lau, Jieying Amelia, Le, Thi Bich Uyen, Wang, Lingzhi, Lee, Miyoung, Kannan, Srinivasaraghavan, Verma, Chandra S, Lim, Chwee Ming, Chng, Wee Joo, Lane, David P, Venkitaraman, Ashok, Hung, Huynh The, Cheok, Chit Fang, Goh, Boon Cher (2020-04-29). Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation. NATURE COMMUNICATIONS 11 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-020-15608-y
Abstract: © 2020, The Author(s). 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.
Source Title: NATURE COMMUNICATIONS
URI: https://scholarbank.nus.edu.sg/handle/10635/175450
ISSN: 20411723
DOI: 10.1038/s41467-020-15608-y
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