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Molecular Cancer Research
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Cancer Genes and Networks

Intron 1–Mediated Regulation of EGFR Expression in EGFR-Dependent Malignancies Is Mediated by AP-1 and BET Proteins

Nathan M. Jameson, Jianhui Ma, Jorge Benitez, Alejandro Izurieta, Jee Yun Han, Robert Mendez, Alison Parisian and Frank Furnari
Nathan M. Jameson
1Ludwig Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, California.
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  • ORCID record for Nathan M. Jameson
Jianhui Ma
1Ludwig Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, California.
2Zeno Pharmaceuticals, San Diego, California.
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  • ORCID record for Jianhui Ma
Jorge Benitez
1Ludwig Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, California.
3Celgene Corporation, San Diego, California.
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Alejandro Izurieta
1Ludwig Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, California.
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Jee Yun Han
4Center for Epigenomics, University of California at San Diego, La Jolla, California.
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Robert Mendez
4Center for Epigenomics, University of California at San Diego, La Jolla, California.
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Alison Parisian
1Ludwig Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, California.
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  • ORCID record for Alison Parisian
Frank Furnari
1Ludwig Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, California.
5The Department of Pathology, University of California San Diego, La Jolla, California.
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  • For correspondence: ffurnari@ucsd.edu
DOI: 10.1158/1541-7786.MCR-19-0747 Published November 2019
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Abstract

The epidermal growth factor receptor (EGFR) is overexpressed in numerous solid tumors and is the subject of extensive therapeutic efforts. Much of the research on EGFR is focused on protein dynamics and downstream signaling; however, few studies have explored its transcriptional regulation. Here, we identified two enhancers (CE1 and CE2) present within the first intron of the EGFR gene in models of glioblastoma (GBM) and head and neck squamous cell carcinoma (HNSCC). CE1 and CE2 contain open chromatin and H3K27Ac histone marks, enhance transcription in reporter assays, and interact with the EGFR promoter. Enhancer genetic deletion by CRISPR/Cas9 significantly reduces EGFR transcript levels, with double deletion exercising an additive effect. Targeted repression of CE1 and CE2 by dCas9-KRAB demonstrates repression of transcription similar to that of genomic deletion. We identify AP-1 transcription factor family members in concert with BET bromodomain proteins as modulators of CE1 and CE2 activity in HNSCC and GBM through de novo motif identification and validate their presence. Genetic inhibition of AP-1 or pharmacologic disruption of BET/AP-1 binding results in downregulated EGFR protein and transcript levels, confirming a role for these factors in CE1 and CE2. Our results identify and characterize these novel enhancers, shedding light on the role that epigenetic mechanisms play in regulating EGFR transcription in EGFR-dependent cancers.

Implications: We identify critical constituent enhancers present in the first intron of the EGFR gene, and provide a rationale for therapeutic targeting of EGFR intron 1 enhancers through perturbation of AP-1 and BET in EGFR-positive malignancies.

This article is featured in Highlights of This Issue, p. 2143

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;17:2208–20

  • Received July 20, 2019.
  • Revision received August 8, 2019.
  • Accepted August 21, 2019.
  • Published first August 23, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (11)
November 2019
Volume 17, Issue 11
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Intron 1–Mediated Regulation of EGFR Expression in EGFR-Dependent Malignancies Is Mediated by AP-1 and BET Proteins
Nathan M. Jameson, Jianhui Ma, Jorge Benitez, Alejandro Izurieta, Jee Yun Han, Robert Mendez, Alison Parisian and Frank Furnari
Mol Cancer Res November 1 2019 (17) (11) 2208-2220; DOI: 10.1158/1541-7786.MCR-19-0747

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Intron 1–Mediated Regulation of EGFR Expression in EGFR-Dependent Malignancies Is Mediated by AP-1 and BET Proteins
Nathan M. Jameson, Jianhui Ma, Jorge Benitez, Alejandro Izurieta, Jee Yun Han, Robert Mendez, Alison Parisian and Frank Furnari
Mol Cancer Res November 1 2019 (17) (11) 2208-2220; DOI: 10.1158/1541-7786.MCR-19-0747
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