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

Li Ren Kong (), Richard Weijie Ong, Tuan Zea Tan, Nur Afiqah Binte Mohamed Salleh, Matan Thangavelu, Jane Vin Chan, Lie Yong Judice Koh, Giridharan Periyasamy, Jieying Amelia Lau, Thi Bich Uyen Le, Lingzhi Wang, Miyoung Lee, Srinivasaraghavan Kannan, Chandra S. Verma, Chwee Ming Lim, Wee Joo Chng, David P. Lane, Ashok Venkitaraman, Huynh The Hung, Chit Fang Cheok and Boon Cher Goh ()
Additional contact information
Li Ren Kong: National University of Singapore
Richard Weijie Ong: Laboratory of Molecular Endocrinology, National Cancer Centre Singapore
Tuan Zea Tan: National University of Singapore
Nur Afiqah Binte Mohamed Salleh: National University of Singapore
Matan Thangavelu: Genome Institute of Singapore, Agency for Science, Technology & Research (A*STAR)
Jane Vin Chan: Genome Institute of Singapore, Agency for Science, Technology & Research (A*STAR)
Lie Yong Judice Koh: Genome Institute of Singapore, Agency for Science, Technology & Research (A*STAR)
Giridharan Periyasamy: Genome Institute of Singapore, Agency for Science, Technology & Research (A*STAR)
Jieying Amelia Lau: National University of Singapore
Thi Bich Uyen Le: Laboratory of Molecular Endocrinology, National Cancer Centre Singapore
Lingzhi Wang: National University of Singapore
Miyoung Lee: University of Cambridge
Srinivasaraghavan Kannan: Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR)
Chandra S. Verma: Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR)
Chwee Ming Lim: National University Cancer Institute, Singapore (NCIS)
Wee Joo Chng: National University of Singapore
David P. Lane: p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR)
Ashok Venkitaraman: University of Cambridge
Huynh The Hung: Laboratory of Molecular Endocrinology, National Cancer Centre Singapore
Chit Fang Cheok: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A*STAR)
Boon Cher Goh: National University of Singapore

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15608-y

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