Addiction of lung cancer cells to GOF p53 is promoted by up-regulation of epidermal growth factor receptor through multiple contacts with p53 transactivation domain and promoter

Oncotarget
Catherine VaughanSumitra Deb

Abstract

Human lung cancers harboring gain-of-function (GOF) p53 alleles express higher levels of the epidermal growth factor receptor (EGFR). We demonstrate that a number of GOF p53 alleles directly upregulate EGFR. Knock-down of p53 in lung cancer cells lowers EGFR expression and reduces tumorigenicity and other GOF p53 properties. However, addiction of lung cancer cells to GOF p53 can be compensated by overexpressing EGFR, suggesting that EGFR plays a critical role in addiction. Chromatin immunoprecipitation (ChIP) using lung cancer cells expressing GOF p53 alleles showed that GOF p53 localized to the EGFR promoter. The sequence where GOF p53 is found to interact by ChIP seq can act as a GOF p53 response element. The presence of GOF p53 on the EGFR promoter increased histone H3 acetylation, indicating a mechanism whereby GOF p53 enhances chromatin opening for improved access to transcription factors (TFs). ChIP and ChIP-re-ChIP with p53, Sp1 and CBP histone acetylase (HAT) antibodies revealed docking of GOF p53 on Sp1, leading to increased binding of Sp1 and CBP to the EGFR promoter. Up-regulation of EGFR can occur via GOF p53 contact at other novel sites in the EGFR promoter even when TAD-I is inactivated; these sites are used by bo...Continue Reading

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Citations

Feb 23, 2020·Biomolecules·Evangelos Pavlakis, Thorsten Stiewe
Apr 30, 2016·Oncotarget·Neil T Pfister, Carol Prives
Dec 14, 2016·Proceedings of the National Academy of Sciences of the United States of America·Fotini VogiatziThorsten Stiewe
Oct 17, 2019·Journal of Neuro-oncology·Asako MizuguchiHideo Takeshima
Nov 1, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Matteo CanalePaola Ulivi
Jan 31, 2021·Nature Communications·Catherine A VaughanSumitra Deb

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Methods Mentioned

BETA
transfection
immunoprecipitation
histone acetylation
ChIP-Seq
ChIP
acetylation
immunoprecipitations
PCR
gene
xenograft

Software Mentioned

Axiovision

Related Concepts

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Addiction

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