4.6 Article

Interleukin-6-mediated epigenetic control of the VEGFR2 gene induces disorganized angiogenesis in human breast tumors

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 34, Pages 12086-12098

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.012590

Keywords

tumor microenvironment; breast cancer; IL-6; myoepithelial cells; DNA methyltransferase 1 (DNMT1); vascular endothelial growth factor receptor 2; angiogenesis; epigenetics; gene regulation interleukin 6 (IL-6); DNA methyltransferase; signal transduction; VEGFR2

Funding

  1. Dr. TMA Pai Foundation scholarship by Manipal Academy of Higher Education, Manipal
  2. Council of Scientific and Industrial Research, Government of India
  3. Pilot Project [6242-P81/RGCB/PMD/DBT/MNBJ/2015]

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Disorganized vessels in the tumor vasculature lead to impaired perfusion, resulting in reduced accessibility to immune cells and chemotherapeutic drugs. In the breast tumor-stroma interplay, paracrine factors such as interleukin-6 (IL-6) often facilitate disordered angiogenesis. We show here that epigenetic mechanisms regulate the crosstalk between IL-6 and vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways in myoepithelial (CD10(+)) and endothelial (CD31(+), CD105(+), CD146(+), and CD133(-)) cells isolated from malignant and nonmalignant tissues of clinically characterized human breast tumors. Tumor endothelial (Endo-T) cells in 3D cultures exhibited higher VEGFR2 expression levels, accelerated migration, invasion, and disorganized sprout formation in response to elevated IL-6 levels secreted by tumor myoepithelial (Epi-T) cells. Constitutively, compared with normal endothelial (Endo-N) cells, Endo-T cells differentially expressed DNA methyltransferase isoforms and had increased levels of IL-6 signaling intermediates such as IL-6R and signal transducer and activator of transcription 3 (STAT3). Upon IL-6 treatment, Endo-N and Endo-T cells displayed altered expression of the DNA methyltransferase 1 (DNMT1) isoform. Mechanistic studies revealed that IL-6 induced proteasomal degradation of DNMT1, but not of DNMT3A and DNMT3B and subsequently led to promoter hypomethylation and expression/activation ofVEGFR2.IL-6-induced VEGFR2 up-regulation was inhibited by overexpression of DNMT1. Transfection of a dominant-negative STAT3 mutant, but not of STAT1, abrogated VEGFR2 expression. Our results indicate that in the breast tumor microenvironment, IL-6 secreted from myoepithelial cells influences DNMT1 stability, induces the expression of VEGFR2 in endothelial cells via a promoter methylation-dependent mechanism, and leads to disordered angiogenesis.

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