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NGFI-A Binding Protein 2 Promotes EGF-Dependent HNSCC Cell Invasion.

ABSTRACT: NGFI-A binding protein 2 (NAB2) represses the transcriptional activation of early growth response protein-1 (EGR1), a tumor-suppressor. However, Epidermal Growth Factor (EGF) promotes tumor progression even with significant EGR1 upregulation. The molecular mechanism through which NAB2 is involved in cancer is largely unknown. Therefore, we evaluated how the NAB2-mediated suppression of EGR1 facilitates head and neck squamous cell carcinoma (HNSCC) cancer progression, in association with Sp1, which competes with EGR1 as a transcriptional regulator. The effect of NAB2 on EGR1/SP1 binding to the consensus promoter sequences of MMP2 and MMP9 was evaluated by chromatin immunoprecipitation (ChIP) and promoter luciferase assay. The correlation between EGR1-NAB2 expression and metastatic status was investigated using The Cancer Genome Atlas (TCGA) for HNSCC patients. Our data showed that NAB2 knockdown in FaDu and YD-10B HNSCC cells alleviated EGF-dependent increase of Matrigel invasion. In addition, NAB2 upregulation in EGF-treated FaDu cell diminishes EGR1 transcriptional activity, resulting in the upregulation of Sp1-dependent tumor-promoting genes. TCGA data analysis of 483 HNSCC tumors showed that higher levels of both EGR1 and NAB2 mRNA were significantly associated with metastasis, corresponding to in vitro results. Our data suggest that NAB2 upregulation facilitates EGF-mediated cancer cell invasion through the transactivation of Sp1-dependent tumor-promoting genes. These results provide insight into the paradoxical roles of EGF-EGR1 in cancer progression.

SUBMITTER: Kim J

PROVIDER: S-EPMC6468740 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:The inhibitory epidermal growth factor receptor (EGFR) antibody, cetuximab, is an approved therapy for head and neck squamous cell carcinoma (HNSCC). Despite tumor response observed in some HNSCC patients, cetuximab alone or combined with radio- or chemotherapy fails to yield long-term control or cures. We hypothesize that a flexible receptor tyrosine kinase coactivation signaling network supports HNSCC survival in the setting of EGFR blockade, and that drugs disrupting this network will provide superior tumor control when combined with EGFR inhibitors. In this work, we submitted EGFR-dependent HNSCC cell lines to RNA interference-based functional genomics screens to identify, in an unbiased fashion, essential protein kinases for growth and survival as well as synthetic lethal targets for combined inhibition with EGFR antagonists. Mechanistic target of rapamycin kinase (MTOR) and erythroblastosis oncogene B (ERBB)3 were identified as high-ranking essential kinase hits in the HNSCC cell lines. MTOR dependency was confirmed by distinct short hairpin RNAs (shRNAs) and high sensitivity of the cell lines to AZD8055, whereas ERBB3 dependency was validated by shRNA-mediated silencing. Furthermore, a synthetic lethal kinome shRNA screen with a pan-ERBB inhibitor, AZD8931, identified multiple components of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, consistent with ERK reactivation and/or incomplete ERK pathway inhibition in response to EGFR inhibitor monotherapy. As validation, distinct mitogen-activated protein kinase kinase (MEK) inhibitors yielded synergistic growth inhibition when combined with the EGFR inhibitors, gefitinib and AZD8931. The findings identify ERBB3 and MTOR as important pharmacological vulnerabilities in HNSCC and support combining MEK and EGFR inhibitors to enhance clinical efficacy in HNSCC. SIGNIFICANCE STATEMENT: Many cancers are driven by nonmutated receptor tyrosine kinase coactivation networks that defy full inhibition with single targeted drugs. This study identifies erythroblastosis oncogene B (ERBB)3 as an essential protein kinase in epidermal growth factor receptor-dependent head and neck squamous cell cancer (HNSCC) cell lines and a synthetic lethal interaction with the extracellular signal-regulated kinase mitogen-activated protein kinase pathway that provides a rationale for combining pan-ERBB and mitogen-activated protein kinase inhibitors as a therapeutic approach in subsets of HNSCC.

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NGFI-A Binding Protein 2 Promotes EGF-Dependent HNSCC Cell Invasion.

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