nach oben

Erschienen in:

27.07.2016 | Original Article

MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer

verfasst von: Jie Cui, Biao Duan, Xuyang Zhao, Yan Chen, Shixun Sun, Wenjie Deng, Yujie Zhang, Jun Du, Yongchang Chen, Luo Gu

Erschienen in: Tumor Biology | Ausgabe 10/2016

Einloggen, um Zugang zu erhalten

Abstract

Hypoxia-inducible factor 2α (HIF2α) plays critical roles in cancer progression. Although the mechanisms of HIF2α translation and degradation have been well studied, the mechanism for HIF2α regulation at transcriptional level is still not fully understood. Here, we present evidence that DNA methylation in promoter contributes to transcription of EPAS1 coding HIF2α. Methylated CpG binding protein 3 (MBD3) contributes to the intricate regulatory mechanism. We showed that MBD3 bound to the EPAS1 promoter in breast cancer cells and amplified EPAS1 transcription through demethylating CpG located around transcriptional start site in MDA-MB-468 cells. This enabled MDA-MB-468 cells to activate HIF2α-mediated angiogenesis. However, in 7860 cells, the demethylation function of MBD3 on EPAS1 was not observed because of the poor methylated-CpG promoter. Nevertheless, depletion of MBD3 induced by shRNA decreased EPAS1 transcription and therefore decreased HIF2α-mediated cellular response in both MDA-MB-468 and 7860 cancer cells. These results indicated that the endogenous MBD3 was involved in regulating the transcription and therefore the transcriptional activities of HIF2α, suggesting that MBD3 may be a potential therapeutic target of tumor.

Nur mit Berechtigung zugänglich

Yoshida Y, Takahashi K, Okita K, Ichisaka T, Yamanaka S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell. 2009;5(3):237–41. doi:10.1016/j.stem.2009.08.001.CrossRefPubMed

Srinivasan S, Chitalia V, Meyer RD, Hartsough E, Mehta M, Harrold I, et al. Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis. 2015;18(4):449–62. doi:10.1007/s10456-015-9468-3.CrossRefPubMedPubMedCentral

De Miguel MP, Alcaina Y, de la Maza DS, Lopez-Iglesias P. Cell metabolism under microenvironmental low oxygen tension levels in stemness, proliferation and pluripotency. Curr Mol Med. 2015;15(4):343–59. doi:10.2174/1566524015666150505160406.CrossRefPubMed

Vogler M, Vogel S, Krull S, Farhat K, Leisering P, Lutz S, et al. Hypoxia modulates fibroblastic architecture, adhesion and migration: a role for HIF-1alpha in cofilin regulation and cytoplasmic actin distribution. PLoS One. 2013;8(7):e69128. doi:10.1371/journal.pone.0069128.CrossRefPubMedPubMedCentral

Dudas J, Schartinger VH, Romani A, Schweigl G, Kordsmeyer K, Marta PI, et al. Cell cycle association and hypoxia regulation of excision repair cross complementation group 1 protein (ERCC1) in tumor cells of head and neck cancer. Tumour Biol. 2014;35(8):7807–19. doi:10.1007/s13277-014-2001-2.CrossRefPubMedPubMedCentral

van den Beucken T, Koch E, Chu K, Rupaimoole R, Prickaerts P, Adriaens M, et al. Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nat Commun. 2014;5:5203. doi:10.1038/ncomms6203.CrossRefPubMedPubMedCentral

Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11(4):335–47. doi:10.1016/j.ccr.2007.02.006.CrossRefPubMedPubMedCentral

Bertout JA, Majmundar AJ, Gordan JD, Lam JC, Ditsworth D, Keith B, et al. HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci U S A. 2009;106(34):14391–6. doi:10.1073/pnas.0907357106.CrossRefPubMedPubMedCentral

Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, et al. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24(5):491–501. doi:10.1101/gad.1881410.CrossRefPubMedPubMedCentral

10.

Kim WY, Perera S, Zhou B, Carretero J, Yeh JJ, Heathcote SA, et al. HIF2 alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Investig. 2009;119(10):3182. doi:10.1172/Jci38443c1.CrossRefPubMedCentral

11.

Devailly DVG, Augert A, Calvé BL, Ferrand M, Pigny P, Payen L, et al. Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth. Oncotarget. 2014;5. doi:10.18632/oncotarget.1681.

12.

Raspaglio G, Petrillo M, Martinelli E, Li Puma DD, Mariani M, De Donato M, et al. Sox9 and Hif-2alpha regulate TUBB3 gene expression and affect ovarian cancer aggressiveness. Gene. 2014;542(2):173–81. doi:10.1016/j.gene.2014.03.037.CrossRefPubMed

13.

Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501–13. doi:10.1016/j.ccr.2009.03.018.CrossRefPubMedPubMedCentral

14.

Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009;8(20):3274–84. doi:10.4161/cc.8.20.9701.CrossRefPubMedPubMedCentral

15.

Micucci C, Matacchione G, Valli D, Orciari S, Catalano A. HIF2alpha is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma. Br J Cancer. 2015;113(8):1178–85. doi:10.1038/bjc.2015.338.CrossRefPubMedPubMedCentral

16.

Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–26. doi:10.1016/0092-8674(92)90611-F.CrossRefPubMed

17.

Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. 2013;14(6):341–56. doi:10.1038/nrm3589.CrossRefPubMedPubMedCentral

18.

Shahrzad S, Bertrand K, Minhas K, Coomber BL. Induction of DNA hypomethylation by tumor hypoxia. Epigenetics. 2007;2(2):119–25. doi:10.4161/epi.2.2.4613.CrossRefPubMed

19.

Liu Q, Liu L, Zhao Y, Zhang J, Wang D, Chen J, et al. Hypoxia induces genomic DNA demethylation through the activation of HIF-1alpha and transcriptional upregulation of MAT2A in hepatoma cells. Mol Cancer Ther. 2011;10(6):1113–23. doi:10.1158/1535-7163.MCT-10-1010.CrossRefPubMed

20.

Pal A, Srivastava T, Sharma MK, Mehndiratta M, Das P, Sinha S, et al. Aberrant methylation and associated transcriptional mobilization of Alu elements contributes to genomic instability in hypoxia. J Cell Mol Med. 2010;14(11):2646–54. doi:10.1111/j.1582-4934.2009.00792.x.CrossRefPubMed

21.

Rawluszko-Wieczorek AA, Horbacka K, Krokowicz P, Misztal M, Jagodzinski PP. Prognostic potential of DNA methylation and transcript levels of HIF1A and EPAS1 in colorectal cancer. Mol Cancer Res. 2014;12(8):1112–27. doi:10.1158/1541-7786.MCR-14-0054.CrossRefPubMed

22.

Yoo S, Takikawa S, Geraghty P, Argmann C, Campbell J, Lin L, et al. Integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD. PLoS Genet. 2015;11(1):e1004898. doi:10.1371/journal.pgen.1004898.CrossRefPubMedPubMedCentral

23.

Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell. 2011;147(7):1498–510. doi:10.1016/j.cell.2011.11.054.CrossRefPubMedPubMedCentral

24.

Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell. 2013;152(5):1146–59. doi:10.1016/j.cell.2013.02.004.CrossRefPubMed

25.

Brown SE, Suderman MJ, Hallett M, Szyf M. DNA demethylation induced by the methyl-CpG-binding domain protein MBD3. Gene. 2008;420(2):99–106. doi:10.1016/j.gene.2008.05.009.CrossRefPubMed

26.

Gunther K, Rust M, Leers J, Boettger T, Scharfe M, Jarek M, et al. Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Res. 2013;41(5):3010–21. doi:10.1093/nar/gkt035.CrossRefPubMedPubMedCentral

27.

Cui Y, Cho IH, Chowdhury B, Irudayaraj J. Real-time dynamics of methyl-CpG-binding domain protein 3 and its role in DNA demethylation by fluorescence correlation spectroscopy. Epigenetics. 2013;8(10):1089–100. doi:10.4161/epi.25958.CrossRefPubMedPubMedCentral

28.

Aranda E, Owen GI. A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the EA.hy926 endothelial cell line. Biol Res. 2009;42(3):377–89. doi:/S0716-97602009000300012.

29.

Lachance G, Uniacke J, Audas TE, Holterman CE, Franovic A, Payette J, et al. DNMT3a epigenetic program regulates the HIF-2alpha oxygen-sensing pathway and the cellular response to hypoxia. Proc Natl Acad Sci U S A. 2014;111(21):7783–8. doi:10.1073/pnas.1322909111.CrossRefPubMedPubMedCentral

30.

Corbet C, Draoui N, Polet F, Pinto A, Drozak X, Riant O, et al. The SIRT1/HIF2alpha axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy. Cancer Res. 2014;74(19):5507–19. doi:10.1158/0008-5472.CAN-14-0705.CrossRefPubMed

31.

Fatrai S, Wierenga ATJ, Daenen SMGJ, Vellenga E, Schuringa JJ. Identification of HIF2 alpha as an important STAT5 target gene in human hematopoietic stem cells. Blood. 2011;117(12):3320–30. doi:10.1182/blood-2010-08-303669.CrossRefPubMed

32.

Purdue MP, Johansson M, Zelenika D, Toro JR, Scelo G, Moore LE, et al. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat Genet. 2011;43(1):60–5. doi:10.1038/ng.723.CrossRefPubMed

33.

Putra AC, Eguchi H, Lee KL, Yamane Y, Gustine E, Isobe T, et al. The A allele at rs13419896 of EPAS1 is associated with enhanced expression and poor prognosis for non-small cell lung cancer. PLoS One. 2015;10(8):e0134496. doi:10.1371/journal.pone.0134496.CrossRefPubMedPubMedCentral

34.

Joshi S, Singh AR, Zulcic M, Durden DL. A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1alpha and HIF2alpha stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res. 2014;12(10):1520–31. doi:10.1158/1541-7786.MCR-13-0682.CrossRefPubMed

35.

Mohlin S, Hamidian A, von Stedingk K, Bridges E, Wigerup C, Bexell D, et al. PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma. Cancer Res. 2015. doi:10.1158/0008-5472.CAN-15-0708.

36.

Moniz S, Bandarra D, Biddlestone J, Campbell KJ, Komander D, Bremm A, et al. Cezanne regulates E2F1-dependent HIF2alpha expression. J Cell Sci. 2015;128(16):3082–93. doi:10.1242/jcs.168864.CrossRefPubMedPubMedCentral

37.

Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 2001;15(6):710–23. doi:10.1101/gad.194101.CrossRefPubMedPubMedCentral

38.

Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature. 2013;502(7469):65–70. doi:10.1038/nature12587.CrossRefPubMed

39.

Cramer JM, Scarsdale JN, Walavalkar NM, Buchwald WA, Ginder GD, Williams Jr DC. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA. J Biol Chem. 2014;289(3):1294–302. doi:10.1074/jbc.M113.512236.CrossRefPubMed

40.

Iurlaro M, Ficz G, Oxley D, Raiber EA, Bachman M, Booth MJ, et al. A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. Genome Biol. 2013;14(10):R119. doi:10.1186/gb-2013-14-10-r119.CrossRefPubMedPubMedCentral

41.

Cui Y, Irudayaraj J. Dissecting the behavior and function of MBD3 in DNA methylation homeostasis by single-molecule spectroscopy and microscopy. Nucleic Acids Res. 2015;43(6):3046–55. doi:10.1093/nar/gkv098.CrossRefPubMedPubMedCentral

42.

Brown SE, Szyf M. Epigenetic programming of the rRNA promoter by MBD3. Mol Cell Biol. 2007;27(13):4938–52. doi:10.1128/MCB.01880-06.CrossRefPubMedPubMedCentral

43.

Sansom OJ, Maddison K, Clarke AR. Mechanisms of disease: methyl-binding domain proteins as potential therapeutic targets in cancer. Nat Clin Pract Oncol. 2007;4(5):305–15. doi:10.1038/ncponc0812.CrossRefPubMed

44.

Crook JM, Dunn NR, Colman A. Repressed by a NuRD. Nat Cell Biol. 2006;8(3):212–4. doi:10.1038/ncb0306-212.CrossRefPubMed

45.

Peng L, Li Y, Xi Y, Li W, Li J, Lv R, et al. Methyl-CpG-binding domain protein 3-like 2 (MBD3L2) promotes Tet2 enzymatic activity for mediating 5mC oxidation. J Cell Sc. 2016. doi:10.1242/jcs.179044.

Titel: MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer
verfasst von: Jie Cui
Biao Duan
Xuyang Zhao
Yan Chen
Shixun Sun
Wenjie Deng
Yujie Zhang
Jun Du
Yongchang Chen
Luo Gu
Publikationsdatum: 27.07.2016
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 10/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-016-5237-1

Neu im Fachgebiet Onkologie

23.04.2024 | Medikamente in Schwangerschaft und Stillzeit | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer

Abstract

Neu im Fachgebiet Onkologie

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 10/2016

Aberrant expression and functions of protocadherins in human malignant tumors

miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes

Disruption of clock gene expression in human colorectal liver metastases

A novel colchicine-based microtubule inhibitor exhibits potent antitumor activity by inducing mitochondrial mediated apoptosis in MIA PaCa-2 pancreatic cancer cells

FBXO25 promotes cell proliferation, invasion, and migration of NSCLC

The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma

Neu im Fachgebiet Onkologie

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie