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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis

Authors: Lupeng Li, Lixiang Wang, Ping Song, Xue Geng, Xiuming Liang, Minran Zhou, Yangyang Wang, Chunyan Chen, Jihui Jia, Jiping Zeng

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear. The histone demethylase retinoblastoma binding protein 2 (RBP2) is involved in gastric tumorgenesis by inhibiting the expression of cyclin-dependent kinase inhibitors (CDKIs).

Methods

The expression of RBP2, VEGF, CD31, CD34 and Ki67 was assessed in 30 human gastric cancer samples and normal control samples. We used quantitative RT-PCR, western blot analysis, ELISA, tube-formation assay and colony-formation assay to characterize the change in VEGF expression and associated biological activities induced by RBP2 silencing or overexpression. Luciferase assay and ChIP were used to explore the direct regulation of RBP2 on the promoter activity of VEGF. Nude mice and RBP2-targeted mutant mice were used to detect the role of RBP2 in VEGF expression and angiogenesis in vivo.

Results

RBP2 and VEGF were both overexpressed in human gastric cancer tissue, with greater microvessel density (MVD) and cell proliferation as compared with normal tissue. In gastric epithelial cell lines, RBP2 overexpression significantly promoted the expression of VEGF and the growth and angiogenesis of the cells, while RBP2 knockdown had the reverse effect. RBP2 directly bound to the promoter of VEGF to regulate its expression by histone H3K4 demethylation. The subcutis of nude mice transfected with BGC-823 cells with RBP2 knockdown showed reduced VEGF expression and MVD, with reduced carcinogenesis and cell proliferation. In addition, the gastric epithelia of RBP2 mutant mice with increased H3K4 trimethylation showed reduced VEGF expression and MVD.

Conclusions

The promotion of gastric tumorigenesis by RBP2 was significantly associated with transactivation of VEGF expression and elevated angiogenesis. Overexpression of RBP2 and activation of VEGF might play important roles in human gastric cancer development and progression.
Appendix
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Literature
1.
Bray F, Jemal A, Grey N, Ferlay J, Forman D: Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol. 2012, 13: 790-801. 10.1016/S1470-2045(12)70211-5CrossRefPubMed
2.
Jemal A, Center MM, DeSantis C, Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010, 19: 1893-1907. 10.1158/1055-9965.EPI-10-0437CrossRefPubMed
3.
Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, Park SR, Fujii M, Kang YK, Chen LT: Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013, 14: e535-e547. 10.1016/S1470-2045(13)70436-4CrossRefPubMed
4.
Gupta SC, Kim JH, Prasad S, Aggarwal BB: Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010, 29: 405-434. 10.1007/s10555-010-9235-2PubMedCentralCrossRefPubMed
5.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011, 144: 646-674. 10.1016/j.cell.2011.02.013CrossRefPubMed
6.
Grothey A, Galanis E: Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol. 2009, 6: 507-518. 10.1038/nrclinonc.2009.110CrossRefPubMed
7.
Gavalas NG, Liontos M, Trachana SP, Bagratuni T, Arapinis C, Liacos C, Dimopoulos MA, Bamias A: Angiogenesis-related pathways in the pathogenesis of ovarian cancer. Int J Mol Sci. 2013, 14: 15885-15909. 10.3390/ijms140815885PubMedCentralCrossRefPubMed
8.
Katoh M: Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review). Int J Mol Med. 2013, 32: 763-767.PubMedCentralPubMed
9.
Ping SY, Shen KH, Yu DS: Epigenetic regulation of vascular endothelial growth factor a dynamic expression in transitional cell carcinoma. Mol Carcinog. 2013, 52: 568-579. 10.1002/mc.21892CrossRefPubMed
10.
Meng F, Onori P, Hargrove L, Han Y, Kennedy L, Graf A, Hodges K, Ueno Y, Francis T, Gaudio E, Francis HL: Regulation of the Histamine/VEGF Axis by miRNA-125b during Cholestatic Liver Injury in Mice. Am J Pathol. 2014, 184: 662-673. 10.1016/j.ajpath.2013.11.008CrossRefPubMed
11.
Ye P, Liu J, He F, Xu W, Yao K: Hypoxia-Induced Deregulation of miR-126 and Its Regulative Effect on VEGF and MMP-9 Expression. Int J Med Sci. 2013, 11: 17-23.PubMedCentralCrossRefPubMed
12.
Chang CP, Bruneau BG: Epigenetics and cardiovascular development. Annu Rev Physiol. 2012, 74: 41-68. 10.1146/annurev-physiol-020911-153242CrossRefPubMed
13.
Ansari KI, Kasiri S, Mandal SS: Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo. Oncogene. 2013, 32: 3359-3370. 10.1038/onc.2012.352PubMedCentralCrossRefPubMed
14.
Park D, Park H, Kim Y, Kim H, Jeoung D: HDAC3 acts as a negative regulator of angiogenesis. BMB Rep. 2013, [Epub ahead of print],
15.
Zeng J, Ge Z, Wang L, Li Q, Wang N, Björkholm M, Jia J, Xu D: The histone demethylase RBP2 Is overexpressed in gastric cancer and its inhibition triggers senescence of cancer cells. Gastroenterology. 2010, 138: 981-992. 10.1053/j.gastro.2009.10.004CrossRefPubMed
16.
Liang X, Zeng J, Wang L, Fang M, Wang Q, Zhao M, Xu X, Liu Z, Li W, Liu S, Yu H, Jia J, Chen C: Histone demethylase retinoblastoma binding protein 2 is overexpressed in hepatocellular carcinoma and negatively regulated by hsa-miR-212. PLoS One. 2013, 8: e69784- 10.1371/journal.pone.0069784PubMedCentralCrossRefPubMed
17.
Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X, Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang QKR, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya EV, Meyerson M, Kaelin WG, Yan Q: Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men. Proc Natl Acad Sci U S A. 2011, 108: 13379-13386. 10.1073/pnas.1110104108PubMedCentralCrossRefPubMed
18.
Suzuki S, Dobashi Y, Hatakeyama Y, Tajiri R, Fujimura T, Heldin CH, Ooi A: Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer. BMC Cancer. 2010, 10: 659-PubMedCentralCrossRefPubMed
19.
Bridges E, Oon CE, Harris A: Notch regulation of tumor angiogenesis. Future Oncol. 2011, 7: 569-588. 10.2217/fon.11.20CrossRefPubMed
20.
Coultas L, Chawengsaksophak K, Rossant J: Endothelial cells and VEGF in vascular development. Nature. 2005, 438: 937-945. 10.1038/nature04479CrossRefPubMed
21.
Fagiani E, Christofori G: Angiopoietins in angiogenesis. Cancer Lett. 2013, 328: 18-26. 10.1016/j.canlet.2012.08.018CrossRefPubMed
22.
Katoh M, Katoh M: WNT signaling pathway and stem cell signaling network. Clin Cancer Res. 2007, 13: 4042-4045. 10.1158/1078-0432.CCR-06-2316CrossRefPubMed
23.
Presta M, Dell'Era P, Mitola S, Moroni E, Ronca R, Rusnati M: Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005, 16: 159-178. 10.1016/j.cytogfr.2005.01.004CrossRefPubMed
24.
Jackson AL, Zhou B, Kim WY: HIF, hypoxia and the role of angiogenesis in non-small cell lung cancer. Expert Opin Ther Targets. 2010, 14: 1047-1057. 10.1517/14728222.2010.511617PubMedCentralCrossRefPubMed
25.
Bzowska M, Mężyk-Kopeć R, Próchnicki T, Kulesza M, Klaus T, Bereta J: Antibody-based antiangiogenic and antilymphangiogenic therapies to prevent tumor growth and progression. Acta Biochim Pol. 2013, 60: 263-275.PubMed
26.
Soffietti R, Trevisan E, Bertero L, Bosa C, Ruda R: Anti-angiogenic approaches to malignant gliomas. Curr Cancer Drug Targets. 2012, 12: 279-288. 10.2174/156800912799277584CrossRefPubMed
27.
Shiva Shankar TV, Willems L: Epigenetic modulators mitigate angiogenesis through a complex transcriptomic network. Vascul Pharmacol. 2014, 60: 57-66. 10.1016/j.vph.2014.01.003CrossRefPubMed
28.
Fujimoto S, Goda T, Mochizuki K: In vivo evidence of enhanced di-methylation of histone H3 K4 on upregulated genes in adipose tissue of diabetic db/db mice. Biochem Biophys Res Commun. 2011, 404: 223-227. 10.1016/j.bbrc.2010.11.097CrossRefPubMed
29.
Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, Baldridge A, Sartorelli V, Zhuang L, Peng W, Ge K: H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife. 2013, 2: e01503- 10.7554/eLife.01503PubMedCentralPubMed
30.
Wu L, Lee SY, Zhou B, Nguyen UT, Muir TW, Tan S, Dou Y: ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes. Mol Cell. 2013, 49: 1108-1120. 10.1016/j.molcel.2013.01.033PubMedCentralCrossRefPubMed
31.
Ge W, Shi L, Zhou Y, Liu Y, Ma GE, Jiang Y, Xu Y, Zhang X, Feng H: nhibition of osteogenic differentiation of human adipose-derived stromal cells by retinoblastoma binding protein 2 repression of RUNX2-activated transcription. Stem Cells. 2011, 29: 1112-1125. 10.1002/stem.663CrossRefPubMed
32.
Sini D, Hansen KH, Christensen J, Agger K, Cloos PA, Helin K: Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev. 2008, 22: 1345-1355. 10.1101/gad.470008CrossRef
33.
Tu S, Teng YC, Yuan C, Wu YT, Chan MY, Cheng AN, Lin PH, Juan LJ, Tsai MD: The ARID domain of the H3K4 demethylase RBP2 binds to a DNA CCGCCC motif. Nat Struct Mol Biol. 2008, 15: 419-421. 10.1038/nsmb.1400CrossRefPubMed
34.
Kashyap V, Ahmad S, Nilsson EM, Helczynski L, Kenna S, Persson JL, Gudas LJ, Mongan NP: The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer. Mol Oncol. 2013, 7: 555-566. 10.1016/j.molonc.2013.01.003PubMedCentralCrossRefPubMed
35.
Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O, Judde JG, Lelievre JD, Levy Y, Benkirane M: NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol Cell. 2012, 48: 445-458. 10.1016/j.molcel.2012.08.022PubMedCentralCrossRefPubMed
36.
Ge Z, Li W, Wang N, Liu C, Zhu Q, Björkholm M, Gruber A, Xu D: Chromatin remodeling: recruitment of histone demethylase RBP2 by Mad1 for transcriptional repression of a Myc target gene, telomerase reverse transcriptase. FASEB J. 2010, 24: 579-586. 10.1096/fj.09-140087CrossRefPubMed
37.
van Oevelen C, Wang J, Asp P, Yan Q, Kaelin WG, Kluger Y, Dynlacht BD: A role for mammalian Sin3 in permanent gene silencing. Mol Cell. 2008, 32: 359-370. 10.1016/j.molcel.2008.10.015PubMedCentralCrossRefPubMed
38.
Cloos PA, Christensen J, Agger K, Helin K: Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 2008, 22: 1115-1140. 10.1101/gad.1652908PubMedCentralCrossRefPubMed
39.
Lopez-Bigas N, Kisiel TA, Dewaal DC, Holmes KB, Volkert TL, Gupta S, Love J, Murray HL, Young RA, Benevolenskaya EV: Genome-wide analysis of the H3K4 histone demethylase RBP2 reveals a transcriptional program controlling differentiation. Mol Cell. 2008, 31: 520-530. 10.1016/j.molcel.2008.08.004PubMedCentralCrossRefPubMed
40.
Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, Basu D, Gimotty P, Vogt T, Herlyn M: A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010, 141: 583-594. 10.1016/j.cell.2010.04.020PubMedCentralCrossRefPubMed
41.
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, McDermott U, Azizian N, Zou L, Fischbach MA, Wong KK, Brandstetter K, Wittner B, Ramaswamy S, Classon M, Settleman J: A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010, 141: 69-80. 10.1016/j.cell.2010.02.027PubMedCentralCrossRefPubMed
42.
Iwamoto M, Friedman EJ, Sandhu P, Agrawal NG, Rubin EH, Wagner JA: Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. Cancer Chemother Pharmacol. 2013, 72: 493-508. 10.1007/s00280-013-2220-zCrossRefPubMed
43.
Højfeldt JW, Agger K, Helin K: Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013, 12: 917-930. 10.1038/nrd4154CrossRefPubMed
44.
Gong W, Wang L, Yao JC, Ajani JA, Wei D, Aldape KD, Xie K, Sawaya R, Huang S: Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res. 2005, 11: 1386-1393. 10.1158/1078-0432.CCR-04-0487CrossRefPubMed
Metadata
Title
Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis
Authors
Lupeng Li
Lixiang Wang
Ping Song
Xue Geng
Xiuming Liang
Minran Zhou
Yangyang Wang
Chunyan Chen
Jihui Jia
Jiping Zeng
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-81

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