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From NF-κB to FACT: Mechanisms and Translational Applications of EGFR-mediated NF-κB Regulation

Dermawan, Josephine Kam Tai
http://orcid.org/0000-0002-1139-2914
http://rave.ohiolink.edu/etdc/view?acc_num=case1436292263

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
The epidermal growth factor receptor (EGFR) drives downstream signaling pathways that promote cancer progression. EGFR is often constitutively active in tumors, e.g., non-small cell lung cancer (NSCLC) and glioblastoma (GBM), either by overexpression or mutations. Nuclear factor-κB (NF-κB) is a master transcription factor that controls inflammation and innate immunity. NF-κB, often constitutively activated in cancer, drives tumor development by activating antiapoptotic and prosurvival genes, and has been implicated in anticancer drug resistance. We and others have shown that EGFR activates NF-κB signaling in both noncancerous and cancer cells. In an attempt to overcome drug resistance to EGFR tyrosine kinase inhibitors (TKI): erlotinib and lapatinib in NSCLC and GBM respectively, we combined EGFR-TKI with a novel class of NF-κB inhibitors, including quinacrine and curaxins, which inhibit NF-κB-driven transcription by targeting the facilitates chromatin transcription (FACT) complex. Unexpectedly, we discovered preferential targeting of GBM stem cells (GSCs), another major player in cancer therapeutic resistance, by curaxins, uncovering a potential role of FACT in the maintenance of stem cell phenotypes. Beyond applications in anticancer therapeutics, we are interested in the basic biological question of how EGFR, compared to canonical NF-κB activators such as interleukin 1 (IL-1), regulates NF-κB distinctively. Specifically, we utilize genomic approaches including RNA-sequencing (RNA-sequencing) and chromatin immunoprecipitation (ChIP)-sequencing to investigate the signal-specific, genome-wide regulation of NF-κB-driven transcription by EGFR versus IL-1. One possible mechanism that underlies specificity in transcription factor regulation is differential phosphorylation. We speculate that phosphorylation of the serine 276 residue on the NF-κB subunit p65 (RELA) plays a role in EGFR-mediated NF-κB regulation. Using the gene editing approach CRISPR, we have introduced the genetic mutation S276A in the RELA gene. In the next phase, we plan to interrogate the impact of this mutation in EGFR-mediated NF-κB regulation. In addition, we will interrogate whether STAT3, a major oncogene also activated by EGFR, serves as a transcriptional coregulator in the context of NF-κB-driven transcription. Taken together, these studies elucidate how EGFR regulates NF-κB on a genomic level, which remains poorly understood, and have major implications in anticancer therapy and drug resistance, especially in cancers driven by EGFR and/or NF-κB.
George Stark, PhD (Advisor)
Mark Jackson, PhD (Committee Chair)
Charis Eng, MD, PhD (Committee Member)
Brian Rubin, MD, PhD (Committee Member)
Micheala Aldred, PhD (Committee Member)
152 p.
Cellular Biology; Genetics; Molecular Biology; Oncology
ChIP-seq; CRISPR; epidermal growth factor receptor, EGFR; curaxins; facilitates chromatin transcription, FACT; glioblastoma; GBM stem cell; nuclear factor kappa B, NF-kappaB; non-small cell lung cancer; quinacrine; RNA-seq; transcriptional regulation

Recommended Citations

Citations

  • Dermawan, J. K. T. (2015). From NF-κB to FACT: Mechanisms and Translational Applications of EGFR-mediated NF-κB Regulation [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1436292263

    APA Style (7th edition)

  • Dermawan, Josephine Kam Tai. From NF-κB to FACT: Mechanisms and Translational Applications of EGFR-mediated NF-κB Regulation. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1436292263.

    MLA Style (8th edition)

  • Dermawan, Josephine Kam Tai. "From NF-κB to FACT: Mechanisms and Translational Applications of EGFR-mediated NF-κB Regulation." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1436292263

    Chicago Manual of Style (17th edition)

case1436292263
338
© 2015, some rights reserved.Creative Commons License From NF-κB to FACT: Mechanisms and Translational Applications of EGFR-mediated NF-κB Regulation by Josephine Kam Tai Dermawan is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.