Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers

Jayanthi P. Gudikote, Tina Cascone, Alissa Poteete, Piyada Sitthideatphaiboon, Qiuyu Wu, Naoto Morikawa, Fahao Zhang, Shaohua Peng, Pan Tong, Lerong Li, Li Shen, Monique Nilsson, Phillip Jones, Erik P. Sulman, Jing Wang, Jean-Christophe Bourdon, Faye M. Johnson, John V. Heymach (Lead / Corresponding author)

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Abstract

Inactivation of p53 is present in almost every tumor, and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53-negative regulators such as MDM2, which mediate the degradation of wildtype p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non–small cell lung cancer and glioblastoma multiforme cell line models, we show that two alternatively spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising exons 1 to 9β or 9γ, respectively) and that lack the C-terminal MDM2-binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense-mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53β and p53γ and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability, and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2-overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups that comprise approximately 6% of all cancers.

Original languageEnglish
Article number101163
Number of pages15
JournalJournal of Biological Chemistry
Volume297
Issue number5
Early online date3 Sep 2021
DOIs
Publication statusPublished - 1 Nov 2021

Keywords

  • p53
  • mRNA decay
  • alternative splicing
  • cancer therapy
  • RNA degradation
  • targeting NMD
  • p53β/γ restoration
  • MDM2

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