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

Abstract

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 of VEGFR2. 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. 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 of VEGFR2. 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. Pathologically activated tissue microenvironment has been shown to shape breast tumor growth, progression, nature, evolution and response to therapy. Persistent proliferation, immune cell recruitment, and angiogenesis are the key determinants of tumor growth (1Hanahan D. Weinberg R.A. Hallmarks of cancer: The next generation.Cell. 2011; 144 (21376230): 646-67410.1016/j.cell.2011.02.013Abstract Full Text Full Text PDF PubMed Scopus (42713) Google Scholar). 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Histone acetyltransferase 7 (KAT7)-dependent intragenic histone acetylation regulates endothelial cell gene regulation.J. Biol. Chem. 2018; 293 (29414790): 4381-440210.1074/jbc.RA117.001383Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 14Pirola L. Ciesielski O. B A. The methylation status of the epigenome: Its emerging role in the regulation of tumor angiogenesis and tumor growth, and potential for drug targeting.Cancers (Basel). 2018; 10: 26810.3390/cancers10080268Crossref Scopus (25) Google Scholar). Earlier studies have shown that critical genes such as VEGF and its receptors, eNOS, MMPs, TMP, TSP, and RECK in maintaining angiogenic homeostasis are influenced by promoter DNA methylation. Inhibitors of DNA methyltransferases (DNMTs) exhibit significant angiostatic effects in various tumor models (14Pirola L. Ciesielski O. B A. The methylation status of the epigenome: Its emerging role in the regulation of tumor angiogenesis and tumor growth, and potential for drug targeting.Cancers (Basel). 2018; 10: 26810.3390/cancers10080268Crossref Scopus (25) Google Scholar, 15Hellebrekers D.M.E.I. Jair K.-W. Viré E. Eguchi S. Hoebers N.T.H. Fraga M.F. Esteller M. Fuks F. Baylin S.B. van Engeland M. Griffioen A.W. Angiostatic activity of DNA methyltransferase inhibitors.Mol. Cancer Ther. 2006; 5 (16505122): 467-47510.1158/1535-7163.MCT-05-0417Crossref PubMed Scopus (84) Google Scholar). Our earlier studies have revealed IL-6 as potential modulator of DNMT isoforms and significantly altered epigenome of endothelial cells (16Balakrishnan A. Guruprasad K.P. Satyamoorthy K. Joshi M. Interleukin-6 determines protein stabilization of DNA methyltransferases and alters DNA promoter methylation of genes associated with insulin signaling and angiogenesis.Lab. Invest. 2018; 98 (29955086): 1143-115810.1038/s41374-018-0079-7Crossref PubMed Scopus (27) Google Scholar). Microarray analysis indicated IL-6–induced significant hypomethylation of VEGFR2 promoter in HUVECs. These findings led us to investigate the paracrine effects of IL-6 derived from CD10+ myoepithelial cells on endothelial cells (CD31+, CD105+; CD133−) in human breast tissue microenvironment. From clinically characterized breast tumors, we isolated cell myoepithelial cells from malignant tissues myoepithelial cells from nonmalignant tissues endothelial cells from malignant tissues and endothelial cells from nonmalignant tissues In cell we the of IL-6 on epigenetic of VEGFR2 expression and its role in normal and tumor associated angiogenesis. In IL-6 elevated to by which was 24 and subsequently increased to The VEGFR2 levels increased to and increased to by of IL-6 We isolated myoepithelial and endothelial cells from the malignant and nonmalignant of human breast tissues to paracrine effects of IL-6 between cell types and myoepithelial cells characterized from with ductal carcinoma and as on Endo-N and Endo-T cells characterized on of and expression of Endo-T cells revealed increased expression of endothelial cell such as and and compared with Endo-N cells. and cells for and the of cell types These cells for expression of and we phenotype in cells. Endo-T cells not express and with Endo-N cells, cells not tumor derived and of and cells characterized by of and by and and IL-6 from a in IL-6 levels in cells compared with cells 9 tumor cell such as and secreted levels cells. analysis indicated elevated levels of to in compared with that of cells and We of and on for the on expression. with higher STAT3 IL-6R neutralizing significantly reduced both and VEGFR2 and levels and that IL-6 in epithelial cell is the key to STAT3 and VEGFR2 expression. We next 3D from and in of cell and compared with cell The results in sprout and in of cell cell IL-6R and VEGFR2 significantly reduced sprout and and that IL-6 and secreted by cells induced angiogenesis. We the mechanisms for VEGFR2 expression in endothelial cells. has been in earlier studies (16Balakrishnan A. Guruprasad K.P. Satyamoorthy K. Joshi M. Interleukin-6 determines protein stabilization of DNA methyltransferases and alters DNA promoter methylation of genes associated with insulin signaling and angiogenesis.Lab. Invest. 2018; 98 (29955086): 1143-115810.1038/s41374-018-0079-7Crossref PubMed Scopus (27) Google of with IL-6 increased DNMT1 levels to to which was to and subsequently decreased to the levels by 24 with of and cells in of IL-6R neutralizing we a significant in DNMT1 expression. The effects of IL-6R was more in endothelial cells with from cells cells and cell IL-6 for the in DNMT1 levels in endothelial cells in tumor microenvironment. of with a transcription degradation of DNMT1 by 2 of with IL-6 for 3 to blocking of transcription not DNMT1 levels of protein by or in cells with IL-6 significant in the levels of DNMT1 by results indicate that regulation of DNMT1 expression by IL-6 is not the of transcription but a or increased expression of VEGFR2 in response to IL-6 is as a of DNMT1 we in of a of of proteasomal IL-6–induced degradation of DNMT1 to the both and expression to IL-6 proteasomal degradation of DNMT1, which subsequently led to of VEGFR2 expression we the levels of IL-6 signaling DNMT and levels in Endo-N and Endo-T cells Endo-T cells elevated expression of IL-6 signaling intermediates such as and of significantly reduced in Endo-T cells compared with Endo-N cells. levels of and not between Endo-N and Endo-T cells. of DNMT protein isoforms such as DNMT1 and DNMT3A significantly elevated in Endo-T cells as to DNMT3B which was in Endo-T cells compared with its normal endothelial cell in tumor microenvironment associated with dynamic in levels of and VEGFR2 significantly increased in Endo-T cells. we the response of Endo-N and Endo-T cells to IL-6 signaling and IL-6 induced in IL-6R levels in Endo-N cells but not in Endo-T cells. Endo-T cells higher levels of analysis revealed both endothelial cell types to IL-6 which led to of to IL-6 in STAT3 expression. to Endo-N cells significant of DNMT1 in response to IL-6 the in levels of DNMT1 the Endo-T cells expressed higher levels of DNMT1 and with IL-6 induced its IL-6 effects on DNMT1 was more in Endo-N cells in Endo-T cells. the cell types to in VEGFR2 expression upon IL-6 In response to we in DNMT1 protein levels and in to of VEGFR2 levels by in HUVECs. These effects abrogated upon with IL-6R neutralizing DNMT1 levels and VEGFR2 levels to that of overexpression of STAT3 in the effects of IL-6 on VEGFR2 expression and We in DNMT1 levels in cells in with cells STAT3 in DNMT1 levels in response to IL-6 IL-6–induced VEGFR2 levels in and STAT3 cells IL-6 increased the of to in cells IL-6 STAT3 is the key for increased of VEGFR2 of STAT3 in VEGFR2 expression was by of with of of STAT3 revealed significant of and levels in or of IL-6 IL-6 has been to we effects of on VEGFR2 expression. We overexpression of not expression of VEGFR2 in both and of STAT3 but not as a key of VEGFR2 overexpression of and not show on DNMT1 These results that IL-6–induced in DNMT1 levels by proteasomal we expression of DNMT isoforms in tumor and normal endothelial cells, we of DNMT isoforms on VEGFR2 gene regulation and protein expression in HUVECs. DNMT1 overexpression abrogated the VEGFR2 expression of VEGFR2 levels in DNMT3A and DNMT3B cells normal and in response to IL-6 DNMT1 but not DNMT3A or DNMT3B are for VEGFR2 expression. of DNMT isoforms by in in VEGFR2 expression blocking of has effects to that of IL-6 on VEGFR2 expression. we IL-6 DNA methylation levels of VEGFR2 promoter in HUVECs. The DNA of the promoter to to on significant hypomethylation of VEGFR2 promoter in response to IL-6 for with levels of a significant was and a to the transcription in the promoter we status of DNA promoter methylation of VEGFR2 gene in Endo-N and Endo-T cells. Endo-T cells from subjects significant hypomethylation compared with in VEGFR2 promoter and and We Endo-T cells displayed increased expression of and more Endo-N cells Cell analysis that of Endo-T cells in and in or of Endo-N cells in and in The of cell for are in we the response of IL-6 in Endo-N and Endo-T cells. The 24 more cells in and cells in in both cell types of IL-6 not significantly the of cells various of cell both in Endo-N and Endo-T cells indicated that the Endo-T cells increased ability to and IL-6 signaling not In Endo-T cells displayed by the in and in of the migration was in The Endo-N cells to the and in response to for cells, migration was in and results with of myoepithelial cells. The with cell for of which was significantly inhibited upon of IL-6R neutralizing with cell was and effects inhibited in of IL-6R neutralizing indicated IL-6 secreted from the endothelial cell the endothelial cell types with epithelial cells with or IL-6R neutralizing In the cells in as indicated in and E. The Endo-N cells with derived from the not the and IL-6R neutralizing not show The Endo-N cells with cells a in and the of migration was decreased to in of IL-6R neutralizing and The Endo-T cells increased with cells and in of IL-6R neutralizing of was in the Endo-T cells with the ability was significantly higher and IL-6R neutralizing decreased to and indicated that the IL-6 secreted by cells induced of endothelial cells in tumor we in endothelial cell that Endo-T cells higher of cells with Endo-N cells which with the In response to Endo-N cells which is a the IL-6 induced phenotype in the Endo-T cells in aggressive We the angiogenic of endothelial cell types in 3D and Endo-T cells higher of and with increased Endo-N cells in the of Upon IL-6 treatment, Endo-N cells in of compared with and was inhibited in of IL-6R neutralizing In response to the tumor endothelial cells to which was associated with the of cells from their and The of IL-6R neutralizing the of IL-6 on tumor endothelial cells and formation of The from Endo-T cells with in significantly and which phenotype In we Endo-T cells to by 2 of Endo-T cells to angiogenic Endo-N cells and increased of formation in response to IL-6 which was abrogated by the of IL-6R neutralizing In response to Endo-T cells their ability to and IL-6R neutralizing formation in cells and and that IL-6 of the potential molecules to disorganized vessels in the tumor microenvironment. IL-6 induces VEGFR2 up-regulation and angiogenesis and we the of VEGFR2 in IL-6 effects on angiogenesis in inhibited by of VEGFR2 blocking in and Endo-N cells in sprout and in response to IL-6 B and and VEGFR2 was to the IL-6 In the Endo-T cells higher of with increased In response to the endothelial cells to the and from the and The VEGFR2 and to the sprout formation in Endo-T cells in of and in the of VEGFR2 the indicated VEGFR2 disorganized angiogenesis as a of IL-6 Our key molecules and mechanisms that disordered angiogenesis in breast tumors. signaling and between IL-6 and VEGFR2 in myoepithelial and endothelial cells in human breast for epigenetic of VEGFR2 gene and its disordered angiogenesis. We that tumor and normal endothelial cells show significant in their and in response to expression of IL-6 intermediates and DNMT patterns of promoter DNA methylation of VEGFR2 gene and increased expression as a of DNMT1 proteasomal IL-6 and of tumor-associated endothelial cells and disorganized which was upon blocking of VEGFR2 and mechanisms have been for inducing neovascularization in and angiogenic and of endothelial cells the A. T. K. of angiogenesis and their in the of tumor growth and 19 PubMed Scopus Google Scholar). breast tumor cells characterized by and expression T. Q. X.Y. N. N. cells with cancer cell with in breast 2013; PubMed Scopus Google Scholar). et T. K. Y. K. D. C. N. K. K. T. N. K. M. M. of tumor-associated endothelial cells in human malignant J. Full Text Full Text PDF PubMed Scopus Google human renal carcinoma of tumor endothelial cells which characterized by compared with of normal cells. In xenograft endothelial cells which displayed that of cells which that the endothelial cells associated with Endo-T cells in not express and that cells not as a of or of of endothelial cells and of increased expression of in Endo-T cells was in with earlier studies M. van C. tumor angiogenesis and in breast PubMed Scopus Google Scholar). DNA have been significantly with dynamic gene expression in various Y. Y. R. Wang J. S. Yang Y. Yang X. of the regulation on the promoter DNA Rep. 2019; 26 Full Text Full Text PDF PubMed Scopus Google Scholar). cells isolated from malignant and nonmalignant of DNA methylation patterns in genes such as and which are in angiogenesis Q. Wang D. Y. S. and expression and methylation of cells from normal and malignant human 2013; PubMed Scopus Google Scholar). Endo-T cells expression of DNMT and in subjects cells significant promoter DNA hypomethylation that was associated with elevated VEGFR2 expression. analysis of VEGFR2 promoter revealed for transcription factors such as STAT1, and Earlier studies have reported and of and for of VEGFR2 angiogenesis Y. Wang E. S. Wang F. T. S. P. R. D. transcription of VEGF in endothelial cells by of the transcription factor Biol. Chem. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. D. G. that PubMed Scopus Google Scholar, de A. the factors to 2013; PubMed Google Scholar, P. R. in cancer and PubMed Scopus Google Scholar). expression of STAT3 reduced expression of STAT3 as of the critical factors that regulate VEGFR2. VEGFR2 is of the key regulators of and angiogenesis and VEGFR2 overexpression was in of and breast tissue J. J. H. J. G. Park Lee J. methylation status of VEGF receptor epigenetic to the of in cancer 7 PubMed Scopus Google Scholar). studies have various mechanisms to epigenetic regulation of VEGFR2. Xu et Y. Wang Y. S. Y. Yang Q. Y. X. X. Wang L. Xu J. Cao Y. et regulates epigenetic in endothelial cells to promote 2017; 9 PubMed Scopus Google have hypomethylation of VEGFR2 promoter was of increased levels and of led to of was to increased endothelial proliferation, migration, and angiogenesis. In of was reported that signaling was of of protein 2 the promoter of VEGFR2 gene X. Zhong J. Zhang S. Zhang Y. Yu Q. Yang P. Wang M.-H. H. Wang D. Wang C.-Y. Loss of protein 2 endothelial angiogenesis and 2011; PubMed Scopus Google Scholar). in in increased VEGFR2 expression and led to proliferation, migration, and angiogenesis X. Zhong J. Zhang S. Zhang Y. Yu Q. Yang P. Wang M.-H. H. Wang D. Wang C.-Y. Loss of protein 2 endothelial angiogenesis and 2011; PubMed Scopus Google Scholar). We that IL-6–induced DNMT1 degradation and VEGFR2 expression are as a of elevated IL-6 levels in tumor microenvironment. IL-6–induced in DNMT1 levels lead to promoter DNA hypomethylation of thus STAT3 to VEGFR2 expression. promoter and are to between DNMT1 and STAT3 regulation of VEGFR2. IL-6 is the key of tumor microenvironment and contributes to crosstalk between tumor cells and which led to and tumor cell growth Q. E. M. A.J. V. D. S. K. D.A. et mediates between tumor cells and activated in the tumor Res. 2018; PubMed Scopus Google Scholar). the of tumor growth in models by blocking IL-6R with and of Q. E. M. A.J. V. D. S. K. D.A. et mediates between tumor cells and activated in the tumor Res. 2018; PubMed Scopus Google Scholar). In of IL-6R by in decreased VEGF which led to reduced tumor further, the cells for and D. A. Zhang K. J.E. of of IL-6 signaling in 2015; PubMed Scopus (27) Google Scholar). breast tumor et R. G. M. expression of and regulates in breast J. 2018; 118 PubMed Scopus (24) Google of IL-6 signaling increased expression which in decreased angiogenesis. with induced expression of and angiogenesis which was associated with VEGF expression. We show that IL-6 accelerated and led to disorganized in Endo-T cells which characterized by phenotype of cells from of IL-6R and VEGFR2 neutralizing the studies have tumor-associated vessel patterns as and disorganized of of tumor endothelial cells N. K. Tumor endothelial cells tumor 2017; PubMed Scopus Google Scholar). The of vessel in has been to levels, drug and immune cell of From to 26 Full Text Full Text PDF PubMed Scopus Google Scholar). of therapy in cancer has been to elevated IL-6 breast cancer subjects elevated IL-6 levels to for experiments of reduced IL-6 levels and subsequently tumor to therapy J. P. K. K. M. S. Y. S. Wang D. et promotes to therapy in breast cancer by IL-6 and 2018; PubMed Scopus Google Scholar). us to blocking IL-6–induced VEGFR2 sprout formation in Endo-T cells. Upon we restoration of sprout formation in the of IL-6 in Endo-T cells. the between tumor myoepithelial and endothelial cells by IL-6 resulting in DNMT1 and increased VEGFR2 expression and disorganized sprout formation in breast tumor microenvironment. both IL-6 and VEGFR2 signaling in resulting in

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