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Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.12.2009 | Original Paper

DNA methylation regulates constitutive expression of Stat6 regulatory genes SOCS-1 and SHP-1 in colon cancer cells

verfasst von: Shuang Bing Xu, Xiao Hong Liu, Ben Hui Li, Yan Zhang, Jia Yuan, Qin Yuan, Pin Dong Li, Xian Zi Yang, Feng Li, Wen Jie Zhang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 12/2009

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Abstract

Purpose

Stat6 signaling is active in cancer cells and IL-4-induced Stat6 activities or Stat6 activational phenotypes vary among cancer cells. This study aimed at investigating possible mechanism(s) involved in the formation of varying Stat6 activities/phenotypes.

Methods

Stat6 regulatory genes, SOCS-1 and SHP-1, were examined for mRNA expression using RT-PCR, and their promoter DNA methylation was assayed by methylation-specific PCR in Stat6-phenotyped colon cancer cell lines. DNA methylation was then verified by sequencing. RT-PCR assay and Western blotting were used to detect the expression of SOCS-1 and SHP-1 after demethylation using 5-aza-2′-deoxycytidine.

Results

Compared with Stat6^null Caco-2 cells, Stat6^high HT-29 cells showed decreased constitutive expression of SOCS-1 and SHP-1, which correlated with DNA hypermethylation in these genes’ promoters. Interestingly, demethylation in HT-29 cells recovered the constitutive expression of SOCS-1 and SHP-1.

Conclusions

These findings suggest that DNA methylation controls the constitutive expression of negative Stat6 regulatory genes, which may affect Stat6 activities.

Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and IL-4 locus accessibility. Annu Rev Immunol 24:607–656. doi:10.1146/annurev.immunol.23.021704.115821 PubMedCrossRef

Baylin S (2001) DNA methylation and epigenetic mechanisms of carcinogenesis. Dev Biol (Basel) 106:85–87

Bruns HA, Kaplan MH (2006) The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol Hematol 57(3):245–253. doi:10.1016/j.critrevonc.2005.08.005 PubMedCrossRef

Dickensheets H, Vazquez N, Sheikh F et al (2007) Suppressor of cytokine signaling-1 is an IL-4-inducible gene in macrophages and feedback inhibits IL-4 signaling. Genes Immun 8:21–27. doi:10.1038/sj.gene.6364352 PubMedCrossRef

Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229PubMed

Fujitake S, Hibi K, Okochi O et al (2004) Aberrant methylation of SOCS-1 was observed in younger colorectal cancer patients. J Gastroenterol 39:120–124. doi:10.1007/s00535-003-1262-0 PubMedCrossRef

Galka E, Thompson JL, Zhang WJ, Poritz LS, Koltun WA (2004) Stat6 (null phenotype) human lymphocytes exhibit increased apoptosis. J Surg Res 122:14–20. doi:10.1016/j.jss.2004.05.004 PubMedCrossRef

Grønbaek K, Hother C, Jones PA (2007) Epigenetic changes in cancer. APMIS 115:1039–1059. doi:10.1111/j.1600-0463.2007.apm_636.xml.x PubMedCrossRef

Hanson EM, Dickensheets H, Qu CK, Donnelly RP, Keegan AD (2003) Regulation of the dephosphorylation of Stat6. Participation of Tyr-713 in the interleukin-4 receptor alpha, the tyrosine phosphatase SHP-1, and the proteasome. J Biol Chem 278:3903–3911. doi:10.1074/jbc.M211747200 PubMedCrossRef

Haque SJ, Harbor P, Tabrizi M, Yi T, Williams BR (1998) Proteintyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction. J Biol Chem 273:33893–33896. doi:10.1074/jbc.273.51.33893 PubMedCrossRef

Hebenstreit D, Horejs-Hoeck J, Duschl A (2005) JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 18:243–249. doi:10.1358/dnp.2005.18.4.908658 PubMedCrossRef

Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A (2006) Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev 3:173–188. doi:10.1016/j.cytogfr.2006.01.004 CrossRef

Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826. doi:10.1073/pnas.93.18.9821 PubMedCrossRef

Issa JP (2007) DNA methylation as a therapeutic target in cancer. Clin Cancer Res 13:1634–1637. doi:10.1158/1078-0432.CCR-06-2076 PubMedCrossRef

Kacha AK, Fallarino F, Markiewicz MA, Gajewski TF (2000) Cutting edge: spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deWcient mice. J Immunol 165:6024–6028PubMed

Li BH, Yang XZ, Li PD et al (2008) IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochem Biophys Res Commun 369:554–560. doi:10.1016/j.bbrc.2008.02.052 PubMedCrossRef

Losman J, Chen XP, Jiang H et al (1999) IL-4 signaling is regulated through the recruitment of phosphatases, kinases, and SOCS proteins to the receptor complex. Cold Spring Harb Symp Quant Biol 64:405–416. doi:10.1101/sqb.1999.64.405 PubMedCrossRef

Momparler RL (2005) Epigenetic therapy of cancer with 5-aza-2′-deoxycytidine (decitabine). Semin Oncol 32:443–451. doi:10.1053/j.seminoncol.2005.07.008 PubMedCrossRef

Nagai H, Naka T, Terada Y et al (2003) Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet 48:65–69. doi:10.1007/s100380300008 PubMedCrossRef

Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17:701–738. doi:10.1146/annurev.immunol.17.1.701 PubMedCrossRef

Ni Z, Lou W, Lee SO et al (2002) Selective activation of members of the signal transducers and activators of transcription family in prostate carcinoma. J Urol 167:1859–1862. doi:10.1016/S0022-5347(05)65249-4 PubMedCrossRef

Oka T, Ouchida M, Koyama M et al (2002) Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 62:6390–6394PubMed

Oshimo Y, Kuraoka K, Nakayama H et al (2004) Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma. Int J Cancer 112:1003–1009. doi:10.1002/ijc.20521 PubMedCrossRef

Ostrand-Rosenberg S, Grusby MJ, Clements VK (2000) Cutting edge: STAT6-deWcient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 165:6015–6019PubMed

Ostrand-Rosenberg S, Sinha P, Clements V et al (2004) Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. Cancer Immunol Immunother 53:86–91. doi:10.1007/s00262-003-0446-z PubMedCrossRef

Rane SG, Reddy EP (2002) JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21:3334–3358. doi:10.1038/sj.onc.1205398 PubMedCrossRef

Ushijima T (2005) Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 5:223–231. doi:10.1038/nrc1571 PubMedCrossRef

Valentino L, Pierre J (2006) JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol 71:713–721. doi:10.1016/j.bcp.2005.12.017 PubMedCrossRef

Weber A, Hengge UR, Bardenheuer W et al (2005) SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene 24:6699–6708. doi:10.1038/sj.onc.1208818 PubMedCrossRef

Wurster AL, Tanaka T, Grusby MJ (2000) The biology of Stat4 and Stat6. Oncogene 19:2577–2584. doi:10.1038/sj.onc.1203485 PubMedCrossRef

Yoshikawa H, Matsubara K, Qian GS et al (2001) SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28:29–35. doi:10.1038/88225 PubMedCrossRef

Yuan Q, Li PD, Li BH et al (2008) Differential Stat6 activities correlate with differential expression of regulatory genes SOCS-1, SHP-1 and PP2A in colon cancer cells. J Cancer Res Clin Oncol 135:131–140. doi:10.1007/s00432-008-0429-8 PubMedCrossRef

Zhang WJ, Koltun WA, Tilberg AF, Thompson JL, Chorney MJ (2003) Genetic control of Interleukin-4-induced activation of the human signal transducer and activator 6 signaling pathway. Hum Immunol 64:402–415. doi:10.1016/S0198-8859(03)00002-8 PubMedCrossRef

Zhang WJ, Koltun WA, Thompson JL et al (2004) Human B lymphoblast cell lines defective of Stat6 signaling produce high levels of proinXammatory cytokines IL-12, TNF-α and IFN-γ. Int J Oncol 24:447–453PubMed

Zhang MS, Zhou YF, Xie CH et al (2006) STAT6 specific shRNA inhibits proliferation and induces apoptosis in colon cancer HT-29 cells. Cancer Lett 243:38–46. doi:10.1016/j.canlet.2005.11.020 PubMedCrossRef

Zhang WJ, Li BH, Yang XZ et al (2008) IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells. Cytokine 42:39–47. doi:10.1016/j.cyto.2008.01.016 PubMedCrossRef

Titel: DNA methylation regulates constitutive expression of Stat6 regulatory genes SOCS-1 and SHP-1 in colon cancer cells
verfasst von: Shuang Bing Xu
Xiao Hong Liu
Ben Hui Li
Yan Zhang
Jia Yuan
Qin Yuan
Pin Dong Li
Xian Zi Yang
Feng Li
Wen Jie Zhang
Publikationsdatum: 01.12.2009
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 12/2009
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-009-0627-z

Springer Medizin

DNA methylation regulates constitutive expression of Stat6 regulatory genes SOCS-1 and SHP-1 in colon cancer cells