Hypermethylation of the <i>CD44</i> gene is associated with progression and metastasis of human prostate cancer

Kito, Hiroki; Suzuki, Hiroyoshi; Ichikawa, Tomohiko; Sekita, Nobuyuki; Kamiya, Naoto; Akakura, Koichiro; Igarashi, Tatsuo; Nakayama, Tsuyoshi; Watanabe, Masatoshi; Harigaya, Kenichi; Itô, Haruo

doi:10.1002/pros.1124

Cited by 68 publications

(42 citation statements)

References 13 publications

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“…CD44 associated to lipid rafts is known to be involved in re-organization of highly dynamic structures of cytoskeleton when cells respond to extracellular stimuli by division and/or changes in shape or activity (83). mRNA and protein expression of CD44 is frequently lost by DNA-methylation in multiple cancers at the early stage of tumour progression (36,51,53,55,(99)(100)(101). Again, re-expression of the CD44 gene is necessary for metastatic diffusion of many tumours (52,98,100,101,109,111).…”

Section: Discussionmentioning

confidence: 99%

“…This is true also in the case of 3-hydroxy-3-methylglutaryl-coenzyme-A-synthase-1 (HMGCS-1), sphingosine acyltransferase, E-cadherin and CD44 (46,(51)(52)(53)(54)(55). The activity of these genes has been shown to be under direct control of promoter-CpG-cytosine-5'C-methylation/ demethylation flux (50)(51)(52)(53)(54)(55)(56). Promoters also contain SRE sites (46) (Tables I and II).…”

Section: Some Raft Component Genes Harbour Sterol Regulatory Elementsmentioning

confidence: 91%

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Epigenetic DNA-methylation regulation of genes coding for lipid raft-associated components: A role for raft proteins in cell transformation and cancer progression (Review)

Patra

Bettuzzi²

2007

Oncol Rep

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Abstract. Metastatic progression is the cause of most cancer deaths. Host tumour cell separation (fission) is accompanied by simultaneous acquisition of migrating capability of cancer cells, remodeling of cellular architecture and effective 'homing' in body host environment. Cell remodeling involves cytoskeletal protein-protein and lipid-protein interaction together with altered signaling. Alteration of signaling in tumour cells may affect expression of many genes also by DNAmethylation/demethylation. This would alter the steady-state intracellular level of structural proteins or metabolic enzymes, and notably enzymes involved in the biosynthesis of lipids, affecting the composition of membranes. Lipid rafts are small, heterogeneous, highly dynamic, sterol-and sphingolipidenriched domains that compartmentalize cellular processes. Small rafts can be stabilized to form larger platforms through protein-protein and protein-lipid interactions. Lipid rafts play an important role in intracellular protein transport, membrane fusion and trans-cytosis, also being platforms for cell surface antigens and adhesion molecules which are crucial for cell activation, polarization and signaling. Detachment of individual tumour cells from the host tumour lump requires lipid-protein-lipid raft (LPLR) reordering. Lipid rafts are also involved in angiogenesis and local invasion, which occurs within the host tumour vicinity by exchange of enzymes, cytokines and motility factors that modify the surrounding extracellular matrix (ECM). Many cell surface adhesion, ECM, and signaling proteins (such as E-cadherin, catenin, CD44, MMP-9 and caveolin-1) are known to be absent or reduced following gene promoter-CpG-island hypermethylation in mid-stage growing tumours, but re-expressed (by gene promoterm CpG-DNA demethylation) in carcinomas such as metastasized lung, prostate and sarcomas. The recent research acquisitions on lipid rafts have tremendous implications in understanding the genetic and biochemical bases of metastatic diffusion of cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Some Raft Component Genes Harbour Sterol Regulatory Elementsmentioning

confidence: 91%

Epigenetic DNA-methylation regulation of genes coding for lipid raft-associated components: A role for raft proteins in cell transformation and cancer progression (Review)

Patra

Bettuzzi²

2007

Oncol Rep

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“…Epigenetic inactivation of tumor suppressor genes through DNA methylation in CpGrich promoter regions contributes to tumorigenesis (Baylin and Herman, 2000;Jones and Baylin, 2002). In prostate cancer, aberrant methylation is involved in the inactivation of various important genes such as E-cadherin, CD44, RASSF1A, GSTP1, the endothelin B receptor, p16, the androgen receptor gene, the retinoic acid receptor beta (RARbeta), the estrogen receptor beta (ER-beta) and the caveolin-1 gene (Lee et al, 1994;Nelson et al, 1997;Cui et al, 2001;Kito et al, 2001;Li et al, 2000Li et al, , 2001Nakayama et al, 2001;Pao et al, 2001;Kuzmin et al, 2002;Liu et al, 2002). When tested, loss of the expression of these genes was associated with CpG island hypermethylation, and expression could be restored after treatment with 5-aza-2 0 -deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene

2003

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Methylation of CpG islands and associated gene silencing may lead to malignant progression, but the mechanisms of CpG island methylation in cancer are unknown. The tazarotene-induced gene 1 (TIG1), also known as retinoid acid (RA) receptor-responsive 1 gene was first identified as an RA-responsive gene and was shown to be downregulated in prostate cancer. Here, we show that this downregulation is caused by the methylation of the promoter and CpG island of TIG1. TIG1 was methylated in 26 of 50 (52%) primary prostate cancers, but was not methylated in normal tissues or benign hyperplasias. Three of four tumors that metastasized, five of six that were poorly differentiated and all that were assigned a Gleason score higher than 8 (7/7) were methylated in the promoter of TIG1. The samples with peripheral invasion were more frequently methylated (21/32, 66%) than tissues without peripheral invasion (5/18, 28%). In addition, Gleason 7-10 cancers (21/30, 70%) were significantly more frequently methylated compared with Gleason 4-6 cancers (4/18, 22%) (Po0.01). The retinoic acid receptor beta (RAR-beta) gene was frequently methylated as well (42/50, 84%). When TIG1 showed methylation, RAR-beta was also methylated (25/26 samples). In almost all samples where RAR-beta was not methylated, TIG1 was also in an unmethylated state (14/15 samples). The methylation of TIG1 and RAR-beta was positively correlated (r ¼ 0.35; P ¼ 0.017). It is possible that the methylation of the retinoid response gene TIG1 occurred in response to the methylation and inactivation of RAR-beta. These observations may contribute to our understanding of mechanistic events leading to CpG island methylation in cancer.

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“…In prostate cancer, aberrant methylation of CpG islands of the CD44 gene, E-cadherin gene and estrogen receptor gene has been associated with tumor progression (Kito et al, 2001;Li et al, 2000Li et al, , 2001. Other genes that have been reported to be hypermethylated in their promoter regions in prostate cancer include the endothelin receptor B (EDNRB) gene, the AR gene and the caveolin-1 gene (Nelson et al, 1997;Pao et al, 2001;Nakayama et al, 2000;Cui et al, 2001).…”

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confidence: 99%

Frequent hypermethylation of the RASSF1A gene in prostate cancer

et al. 2002

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Recently, we have cloned and characterized the Ras association domain family 1A gene (RASSF1A) at 3p21.3, from which loss of genetic material is one of the most frequent events in several types of human solid tumors. The CpG island promoter region of this gene is highly methylated in several human cancers, most notably in small cell lung cancer, breast cancer, and renal cell carcinoma. In this study, we have analysed the methylation status of RASSF1A in primary prostate tumors and in the prostate cancer cell line LNCaP. In total, 37 out of 52 tumors (71%) were methylated at the promoter region of RASSF1A. The relative frequency of methylation was higher in more aggressive tumors compared with less malignant tumors. For instance, tumors with a Gleason score of 7 -10 (25 out of 30, 83%) were significantly more methylated compared with Gleason 4 -6 tumors (11 out of 20, 55%, P=0.032, Fisher's exact test). Coincident with a hypermethylated promoter, transcripts of RASSF1A were missing in LNCaP cells. Expression of RASSF1A was restored with 5-aza-2'-deoxycytidine, a DNA methylation inhibitor. In conclusion, our data suggest that epigenetic inactivation of RASSF1A by methylation is a very common event in prostate cancer and might be involved in the progression of the disease. Testing for RASSF1A methylation should become useful in prostate cancer early detection and diagnosis and might aid prognosis by gauging the potential status of progression.

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Hypermethylation of the CD44 gene is associated with progression and metastasis of human prostate cancer

Abstract: These results indicate an important role of CD44 methylation in the progression and metastasis of prostate cancer, although the amount of methylational heterogeneity is substantial among metastatic sites within the same patient.

Cited by 68 publications

References 13 publications

Epigenetic DNA-methylation regulation of genes coding for lipid raft-associated components: A role for raft proteins in cell transformation and cancer progression (Review)

Epigenetic DNA-methylation regulation of genes coding for lipid raft-associated components: A role for raft proteins in cell transformation and cancer progression (Review)

Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene

Frequent hypermethylation of the RASSF1A gene in prostate cancer

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