Epigenetic Regulation of the KAI1 Metastasis Suppressor Gene in Human Prostate Cancer Cell Lines

Sekita, Nobuyuki; Suzuki, Hiroyoshi; Ichikawa, Tomohiko; Kito, Hiroki; Akakura, Koichiro; Igarashi, Tatsuo; Nakayama, Tsuyoshi; Watanabe, Masatoshi; Shiraishi, Taizo; Toyota, Minoru; Yoshie, Osamu; Itô, Haruo

doi:10.1111/j.1349-7006.2001.tb01185.x

Cited by 41 publications

(20 citation statements)

References 14 publications

(13 reference statements)

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“…In the present study, and NL9980 cells by bisulfite sequencing, while the MSP assay demonstrated non-methylation of KAI1 promoter in these two cell lines. There were reports from several groups suggested that methylation may not the key mechanism for reduction of KAI1 expression, which suggest that other pathway was involved in KAI1 regulation (21,37,38). Taken together, these result implicated that KAI1 was not methylated at least in cancer cell NL9980 or L9981.…”

Section: Discussionmentioning

confidence: 78%

Nm23-H1 was involved in regulation of KAI1 expression in high-metastatic lung cancer cells L9981

et al. 2016

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Background:The tetraspanin KAI1/CD82 was identified as a tumor metastasis suppressor that downregulated in malignant progression of lung cancer. However, the underlying mechanism of anti-metastasis role of KAI1 in lung cancer is hardly known. In this paper, we sought to study the function and regulatory mechanism of KAI1 in high metastasis lung cancer cell line.Methods: KAI1 expression was detected in high/low metastatic large lung cancer cell line L9981/NL9980 by quantitative real-time polymerase chain reaction (qRT-PCR). The tumor suppressor function of KAI1 was determined by wound healing assay after over-expression or knockdown of KAI1 in L9981 or NL9980 cells.Invasion assay was performed to detect the invasion ability of L9981 by transfection of KAI1. The effect of tumor suppressor p53 on KAI1 expression was measured by western blot and luciferase assay. Then the regulation of KAI1 due to over-expression of metastasis suppressor nm23-H1 was monitored by qRT-PCR, western blot and reporter gene assay. The progression of L9981 cells after p53 and nm23-H1 expression was detected by invasion assay. Also, methylation status of KAI1 promoter in NL9980 and L9981 cells were examined by bisulfite sequencing and methylation-specific PCR.Results: We found that KAI1 is down-regulated in high metastatic L9981 cells compare with NL9980 cells. The migration and invasion of L9981 cells were remarkably suppressed in vitro by KAI1 transfection.The migration ability of NL9980 was enhanced by inhibition of KAI1. Furthermore, KAI1 expression was induced after over-expression of p53 or nm23-H1, while cell invasion was inhibited in L9981 cells. The results of reporter analysis indicated that KAI1 promoter region between −922 to −846 could response to nm23-H1. In addition, we discovered only slight methylation of KAI1 promoter, which showed that loss expression of KAI1 in L9981 cells may not due to promoter methylation. Conclusions:The results suggested that nm23-H1 was involved in the KAI1-regulated inhibition of metastasis in lung cancer cells. More insights into the relationship between KAI1 and other metastasis suppressors will pave the way for the elucidation of anti-metastasis mechanism in lung cancer.

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Section: Discussionmentioning

confidence: 78%

Nm23-H1 was involved in regulation of KAI1 expression in high-metastatic lung cancer cells L9981

et al. 2016

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“…Trainer and co-workers later showed that treatment of murine melanoma cells with the DNA de-methylating agent 5-azacytidine resulted in reversible reduction of metastatic lung colonization (43). Recent studies have shown that treatment of cells with 5-azacytidine can induce expression of the metastasis suppressor genes Nm23 (44) and KAI1 (45). Links between metastasis and HDAC activity first became apparent when the breast cancer metastasis promoting gene, MTA1, was identified as a component of the NuRD⅐HDAC complex (46,47).…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Metastasis Suppressor 1 (BRMS1) Forms Complexes with Retinoblastoma-binding Protein 1 (RBP1) and the mSin3 Histone Deacetylase Complex and Represses Transcription

Meehan

Samant

Hopper

et al. 2004

Journal of Biological Chemistry

159

139

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Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple human and murine cancer cells without inhibiting tumorigenicity. By yeast two-hybrid and co-immunoprecipitation, BRMS1 interacts with retinoblastoma binding protein 1 and at least seven members of the mSin3 histone deacetylase (HDAC) complex in human breast and melanoma cell lines. BRMS1 co-immunoprecipitates enzymatically active HDAC proteins and represses transcription when recruited to a Gal4 promoter in vivo. BRMS1 exists in large mSin3 complex(es) of ϳ1.4 -1.9 MDa, but also forms smaller complexes with HDAC1. Deletion analyses show that the carboxyl-terminal 42 amino acids of BRMS1 are not critical for interaction with much of the mSin3 complex and that BRMS1 appears to have more than one binding point to the complex. These results further show that BRMS1 may participate in transcriptional regulation via interaction with the mSin3⅐HDAC complex and suggest a novel mechanism by which BRMS1 might suppress cancer metastasis.The complex process of cancer cell dissemination and the establishment of secondary foci involves the acquisition of multiple abilities by metastatic cells. For example, blood-borne metastasis requires cells to invade from the primary tumor, enter the circulation, survive transport, arrest at a secondary site, recruit a blood supply, and proliferate at that site (1). The ability to accomplish all of these steps likely involves changes in, and coordinated expression of, a large assortment of genes. Consistent with this notion, several genes, proteins, and pathways have been associated with metastatic progression, including oncogenes, motility factors, and matrix metalloproteinases (1, 2). In addition to metastasis-promoting genes, a new class of molecules called metastasis suppressors has been described (reviewed in Refs. 2-5). By definition, metastasis suppressors inhibit metastasis without blocking primary tumor growth, presumably by inhibiting one or more steps necessary for metastasis. To date, 13 metastasis suppressor genes have been identified that reduce the metastatic ability of cancer cell line(s) in vivo without affecting tumorigenicity, namely breast cancer metastasis suppressor 1 (BRMS1), 1 CRSP3, DRG1, KAI1, KISS1, MKK4, NM23, RhoGDI2, RKIP, SSeCKs, VDUP1, E-cadherin, and TIMPs (reviewed in Refs. 4 and 5).We identified BRMS1 using differential display to compare highly metastatic breast carcinoma cells with related but metastasis-suppressed cells (6). Enforced expression of BRMS1 suppressed metastasis in three animal models, namely human breast (6), murine mammary (7), and human melanoma cells (8). Additionally, BRMS1 mapped to loci in murine (7) and human (6) genomes that had previously been implicated in metastasis control (9). The BRMS1 protein localized to nuclei and restored gap junctional intercellular communication in both breast and melanoma tumor cell lines (8,10,11), but its molecular functions remain to be elucidated.One approach to determine a mechanism of action involves identifying which...

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“…However, the underlying cause for loss of KAI1 expression in advanced tumours and tumour cell lines remains unknown. Available evidence suggests that mechanisms including loss of heterozygosity at the KAI1 locus on human chromosome 11p11.2, gene or promoter mutation and promoter hypermethylation are not responsible (Dong et al, 1996;Tagawa et al, 1999;Liu et al, 2000;Miyazaki et al, 2000;Sekita et al, 2001). Another possible explanation is that loss of KAI1 expression might reflect altered transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

et al. 2004

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A molecular mechanism to explain reduced KAI1 expression in invasive and metastatic tumour cells remains elusive. In this report, we extend an earlier study in bladder cells to confirm that a 76 bp region of the KAI1 promoter (residues À922 to À847), with binding motifs for p53, AP1 and AP2, is required for high level activity of a KAI1 reporter in prostate cancer cell lines. Gel shift and supershift experiments supported binding of p53, junB and heterodimers of AP2a/AP2c or AP2b/AP2c to this sequence. Introduction of mutations into specific motifs demonstrated an essential requirement for p53 and junB to reporter activity, and that functional synergy between these two factors enhanced activity. A further elevation of reporter activity required AP2. Roles of individual p53, junB and AP2 proteins, as well as functional synergy between p53 and junB, were confirmed in transfection experiments. Western blotting analysis showed that an absence of wild-type p53, and/or a loss of junB and AP2 protein expression, correlated with downregulation of KAI1 mRNA levels in a series of prostate cancer cell lines. A loss of p53 function and/or expression of junB, combined with reduced expression of specific AP2 proteins may underly downregulated KAI1 expression in tumour cells.

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Epigenetic Regulation of the KAI1 Metastasis Suppressor Gene in Human Prostate Cancer Cell Lines

Cited by 41 publications

References 14 publications

Nm23-H1 was involved in regulation of KAI1 expression in high-metastatic lung cancer cells L9981

Nm23-H1 was involved in regulation of KAI1 expression in high-metastatic lung cancer cells L9981

Breast Cancer Metastasis Suppressor 1 (BRMS1) Forms Complexes with Retinoblastoma-binding Protein 1 (RBP1) and the mSin3 Histone Deacetylase Complex and Represses Transcription

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

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