Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma

Yamashita, Keishi; Upadhyay, Sunil; Osada, Motonobu; Hoque, Mohammad O.; Yan, Xuemin; Mori, Masaki; Sato, Fumiaki; Meltzer, Stephen J.; Sidransky, David

doi:10.1016/s1535-6108(02)00215-5

Cited by 299 publications

(311 citation statements)

References 53 publications

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“…We extracted genomic DNA and carried out bisulphite modification of genomic DNA as described previously (Yamashita et al, 2002). Briefly, 2 mg of DNA in 20 ml of H 2 O containing 5 mg of salmon sperm DNA were denatured by incubation with 0.3 M NaOH at 501C for 20 min.…”

Section: Bisulphite Treatmentmentioning

confidence: 99%

Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer

et al. 2008

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We previously cloned human G protein gamma 7 (GNG7) and demonstrated that it was downregulated in gastrointestinal cancer. The significance of GNG7 expression in oesophageal cancer is unknown. TaqMan quantitative real-time PCR was performed to determine the clinical significance of GNG7 expression in 55 cases of oesophageal cancer. Furthermore, GNG7-transfected oesophageal cancer cells were analysed in laboratory studies at genomic and epigenetic levels. Twenty-seven patients with low GNG7 expression showed significantly poorer survival than did 28 patients with high expression (Po0.05). Tumours with low GNG7 expression invaded deeper than those with high GNG7 expression (Po0.05), both in vivo and in vitro. Eight tumours retained GNG7 expression, and they did not show either promoter hypermethylation or loss of heterozygosity (LOH). In 38 tumours with GNG7 suppression, 22 (57%) showed either LOH or promoter hypermethylation. In addition, GNG7 expression was significantly associated with the presence of miR328 in oesophageal cancer cell lines, which suggests that this microRNA might be a regulator of GNG7 expression. GNG7 suppression represents a new prognostic indicator in cases of oesophageal cancer. GNG7 might be suppressed by LOH and promoter hypermethylation or by microRNA.

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Section: Bisulphite Treatmentmentioning

confidence: 99%

Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer

et al. 2008

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“…Initially, significant progress was made by functional epigenomic approaches using gene expression microarrays to study changes in gene expression following global demethylation of cancer cell line genomes (Yamashita et al, 2002;Sato et al, 2003;Lodygin et al, 2005). For RCC, this approach resulted in the identification of B14 candidate RCC TSGs (Morris et al, 2005(Morris et al, , 2010Ibanez de Caceres et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

et al. 2010

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The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with highdensity expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P ¼ 0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.

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“…Of these modifications, acetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs) which control gene expression by remodeling the nucleosomes leading to either transcriptional activation or repression, respectively (Kondo et al, 2004). Two chemical agents commonly used to modulate the expression of silenced genes in cancer cells are 5-aza-2 0 -deoxycytitdine (5-aza-dC), which is an inhibitor of DNA methylation and trichostatin A (TSA), an inhibitor of histone deacetylation (Marks et al, 2001;Johnstone, 2002;Yamashita et al, 2002). Gene expression studies revealed that the effects of 5-aza-dC are similar to those of TSA exposure than either of the somatic cell DNA methyltransferase knockouts (DNMT knockouts), implying a converging mechanism for these agents (Gius et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

et al. 2007

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To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2 0 -deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P ¼ 0.0146, v 2 test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

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Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma

Cited by 299 publications

References 53 publications

Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer

Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

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