title: PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis.
abstract: Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5'CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5'CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (gamma=-1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5'CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.forename: Chengjun
authors.initials: C
authors.lastname: Zhou
authors.forename: Chunhong
authors.initials: C
authors.lastname: Ma
authors.forename: Wensheng
authors.initials: W
authors.lastname: Sun
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014410:Tumor Stem Cell Assay
chemical_list: D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14037-42
references.pmid: 10570194
references.citation: Oncogene. 2004 Oct 21;23(49):8135-45
references.pmid: 15361828
references.citation: Mol Cancer Ther. 2006 Apr;5(4):1041-9
references.pmid: 16648576
references.citation: J Neurosurg. 2000 Dec;93(6):932-9
references.pmid: 11117865
references.citation: J Korean Med Sci. 2000 Oct;15(5):555-9
references.pmid: 11068994
references.citation: Nat Med. 1995 Jul;1(7):686-92
references.pmid: 7585152
references.citation: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2005 Oct;27(5):597-600
references.pmid: 16274040
references.citation: Eur J Gastroenterol Hepatol. 2007 Nov;19(11):952-61
references.pmid: 18049164
references.citation: J Biol Chem. 2008 Jan 11;283(2):1026-33
references.pmid: 17991735
references.citation: Technol Cancer Res Treat. 2006 Jun;5(3):185-94
references.pmid: 16700615
references.citation: J Pathol. 2003 Aug;200(5):640-6
references.pmid: 12898601
references.citation: Oncogene. 2008 Mar 6;27(11):1527-35
references.pmid: 17828298
references.citation: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):185-93
references.pmid: 12162432
references.citation: Gene. 1995 Dec 12;166(2):297-301
references.pmid: 8543179
references.citation: Oncogene. 2004 Sep 30;23(45):7484-93
references.pmid: 15334056
references.citation: Bioinformatics. 2002 Nov;18(11):1427-31
references.pmid: 12424112
references.citation: Oncogene. 2002 Aug 12;21(35):5400-13
references.pmid: 12154403
references.citation: Science. 2006 Oct 20;314(5798):467-71
references.pmid: 17053147
references.citation: J Immunol. 2006 Dec 1;177(11):8095-102
references.pmid: 17114484
references.citation: Cancer Res. 2004 Oct 1;64(19):6892-9
references.pmid: 15466178
references.citation: Trends Genet. 2000 Apr;16(4):168-74
references.pmid: 10729832
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
references.pmid: 8790415
references.citation: Oncogene. 2008 Apr 3;27(15):2128-36
references.pmid: 17968323
references.citation: Mol Cancer Ther. 2004 Feb;3(2):103-10
references.pmid: 14985450
references.citation: Biochem Biophys Res Commun. 2002 Sep 13;297(1):78-82
references.pmid: 12220511
references.citation: Cancer Res. 2005 Jul 15;65(14):6034-41
references.pmid: 16024603
references.citation: Cancer Res. 2005 Apr 1;65(7):2565-71
references.pmid: 15805250
references.citation: J Microbiol Methods. 2006 Oct;67(1):36-43
references.pmid: 16631263
references.citation: Hum Pathol. 2005 Sep;36(9):1008-15
references.pmid: 16153465
references.citation: Gene Ther. 2007 Sep;14(18):1353-61
references.pmid: 17611588
references.citation: Mol Cell Biol. 2003 Jan;23(1):26-37
references.pmid: 12482958
references.citation: Oncogene. 2006 Oct 5;25(45):6101-12
references.pmid: 16682950
references.citation: Oncogene. 2002 Aug 12;21(35):5427-40
references.pmid: 12154405
references.citation: Mol Cell Biol. 2006 Feb;26(4):1297-306
references.pmid: 16449643
references.citation: Cell Mol Biol (Noisy-le-grand). 1997 Dec;43(8):1227-34
references.pmid: 9489949
references.citation: Acta Neuropathol. 2003 Nov;106(5):479-85
references.pmid: 12904991
references.citation: Oncol Rep. 2007 Jan;17(1):123-8
references.pmid: 17143488
references.citation: Oncogene. 2001 Jan 11;20(2):231-9
references.pmid: 11313950
references.citation: Oncogene. 2003 Jun 12;22(24):3712-20
references.pmid: 12802278