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SATB1 as oncogenic driver and potential therapeutic target in head & neck squamous cell carcinoma (HNSCC).

ABSTRACT: The Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer protein that controls gene expression of numerous genes by regulating chromatin architecture and targeting chromatin-remodeling/-modifying enzymes onto specific chromatin regions. SATB1 is overexpressed in various tumors. In head and neck squamous cell carcinoma (HNSCC), SATB1 upregulation is correlated with TNM classification, metastasis, poor prognosis and reduced overall survival. In this paper, we comprehensively analyze cellular and molecular effects of SATB1 in a large set of primary cell lines from primary HNSCC or metastases, using RNAi-mediated knockdown in vitro and, therapeutically, in tumor xenograft mouse models in vivo. In a series of 15 cell lines, major differences in SATB1 levels are observed. In various 2-D and 3-D assays, growth inhibition upon efficient siRNA-mediated SATB1 knockdown depends on the cell line rather than initial SATB1 levels. Inhibitory effects are found to be based on cell cycle deceleration, apoptosis induction, decreased HER3 and Heregulin A&B expression, and effects on EMT genes. In vivo, systemic treatment of tumor xenograft-bearing mice with siRNAs formulated in polymeric nanoparticles inhibits tumor growth of two HNSCC xenograft models, resulting from therapeutic SATB1 reduction and concomitant decrease of proliferation and induction of apoptosis. In conclusion, SATB1 represents a promising target in HNSCC, affecting crucial cellular processes and molecular pathways.

SUBMITTER: Panchal O

PROVIDER: S-EPMC7248088 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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SATB1 as oncogenic driver and potential therapeutic target in head & neck squamous cell carcinoma (HNSCC).

Panchal Omkar O Wichmann Gunnar G Grenman Reidar R Eckhardt Lisa L Kunz-Schughart Leoni A LA Franke Heike H Dietz Andreas A Aigner Achim A

Scientific reports 20200525 1

The Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer protein that controls gene expression of numerous genes by regulating chromatin architecture and targeting chromatin-remodeling/-modifying enzymes onto specific chromatin regions. SATB1 is overexpressed in various tumors. In head and neck squamous cell carcinoma (HNSCC), SATB1 upregulation is correlated with TNM classification, metastasis, poor prognosis and reduced overall survival. In this paper, we comprehensively an ...[more]

PMID: 32451408

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Project description:BackgroundOverexpression of epidermal growth factor receptor (EGFR), and downstream pathway activation appears to be a common oncogenic driver in the majority of head and neck squamous cell cancers (HNSCCs); yet targeting EGFR for the treatment of HNSCC has met with limited success. Apart from the anti-EGFR antibody cetuximab, no small molecule EGFR/tyrosine kinase inhibitors (TKIs) have progressed to routine clinical use. The aim of this study was to determine factors contributing to the lack of response to TKIs and identify alternative therapeutic vulnerabilities.MethodsGenomic and transcriptomic sequencing, high-throughput compound screens, overexpression and siRNA knockdown, western blot, in vivo xenograft studies.FindingsWe derived three pairs of isogenic gefitinib (TKI)-sensitive and resistant patient-derived HNSCC cell lines. Genomic sequencing of gefitinib-resistant cell lines identified a lack of activating and resistance-associated EGFR mutations. Instead, transcriptomic sequencing showed upregulated EMT gene signature in the gefitinib-resistant cells with a corresponding increase in their migratory phenotype. Additionally, the resistant cell displayed reduced growth rate. Surprisingly, while gefitinib-resistant cells were independent of EGFR for survival, they nonetheless displayed activation of downstream ERK and AKT signalling. High-throughput screening (HTS) of druggable, small molecule libraries revealed that the gefitinib-resistant cells were particularly sensitive to inhibitors of genes involved in cell cycle and mitosis, such as Aurora kinase inhibitors (AKIs), cyclin-dependent kinase (CDK) inhibitors, and microtubule inhibitors. Notably our results showed that in the EGFR inhibited state, Aurora kinases are essential for cell survival.InterpretationOur study demonstrates that in the absence of activating EGFR mutations, HNSCCs may gain resistance to gefitinib through decreased cell proliferation, which makes them exceptionally vulnerable to cell-cycle inhibitors.FundingAgency for Science, Technology, and Research (A*STAR), National Medical Research Council (NMRC), and the National Institutes of Health (NIH)/National Cancer Institute (NCI).

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SATB1 as oncogenic driver and potential therapeutic target in head & neck squamous cell carcinoma (HNSCC).

Publications

SATB1 as oncogenic driver and potential therapeutic target in head & neck squamous cell carcinoma (HNSCC).

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