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Cell Rep. 2016 Feb 23;14(7):1774-1786. doi: 10.1016/j.celrep.2016.01.056. Epub 2016 Feb 11.

Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.

Author information

1
Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
2
Center for Systems and Computational Biology, the Wistar Institute, Philadelphia, PA 19104, USA.
3
Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
4
Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
5
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), C1428ADN Buenos Aires, Argentina.
6
Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.

Abstract

Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.

PMID:
26876172
PMCID:
PMC4767618
DOI:
10.1016/j.celrep.2016.01.056
[Indexed for MEDLINE]
Free PMC Article

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