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

TY - JOUR

T1 - Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers

AU - Gudikote, Jayanthi P.

AU - Cascone, Tina

AU - Poteete, Alissa

AU - Sitthideatphaiboon, Piyada

AU - Wu, Qiuyu

AU - Morikawa, Naoto

AU - Zhang, Fahao

AU - Peng, Shaohua

AU - Tong, Pan

AU - Li, Lerong

AU - Shen, Li

AU - Nilsson, Monique

AU - Jones, Phillip

AU - Sulman, Erik P.

AU - Wang, Jing

AU - Bourdon, Jean-Christophe

AU - Johnson, Faye M.

AU - Heymach, John V.

N1 - This work was supported by University of Texas Lung Spore P50CA070907, Lung Cancer Moon Shot, Jane Ford Petrin Fund for KRAS Research and Lung Cancer Research Foundation grants, awarded to J.V.H, and CCSG P30CA016672. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2021/11/1

Y1 - 2021/11/1

N2 - 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.

AB - 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.

KW - p53

KW - mRNA decay

KW - alternative splicing

KW - cancer therapy

KW - RNA degradation

KW - targeting NMD

KW - p53β/γ restoration

KW - MDM2

UR - https://www.scopus.com/pages/publications/85119013353

U2 - 10.1016/j.jbc.2021.101163

DO - 10.1016/j.jbc.2021.101163

M3 - Article

C2 - 34481841

SN - 0021-9258

VL - 297

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 5

M1 - 101163

ER -