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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Female
  • Galectin 1 / genetics
  • Galectin 1 / immunology
  • Gene Expression Regulation, Neoplastic*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Immune Tolerance
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Matrix Attachment Region Binding Proteins / antagonists & inhibitors
  • Matrix Attachment Region Binding Proteins / genetics
  • Matrix Attachment Region Binding Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Neoplasm Transplantation
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / immunology
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / immunology
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / immunology

Substances

  • Galectin 1
  • Histocompatibility Antigens Class II
  • Histones
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Interleukin-6
  • Matrix Attachment Region Binding Proteins
  • Notch1 protein, mouse
  • RNA, Small Interfering
  • Rbpj protein, mouse
  • Receptor, Notch1
  • Satb1 protein, mouse
  • Transcription Factors
  • Zbtb46 protein, mouse
  • histone H2B type 1-A
  • interleukin-6, mouse