HLA-B down-regulation in human melanoma is mediated by sequences located downstream of the transcription-initiation site

Griffioen, Marieke; Ouwerkerk, Ilse J.M.; Harten, Veronique; Schrier, Peter I.

doi:10.1002/(sici)1097-0215(19990209)80:4<573::aid-ijc15>3.0.co;2-s

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…Demethylation and re-expression of the HLA-B gene was obtained by treatment with 5-aza-2Ј-deoxycytidine in one of the esophageal cell lines, suggesting that DNA methylation was responsible for mRNA inactivation in this cell line. The HLA-B locus was most frequently hypermethylated, which is consistent with the observation that in human tumors down-regulation of HLA class I expression was B locusspecific (33). There was a high concurrence among all three HLA genes, which is similar to the case of the 9p21 gene cluster, where the p14 ARF , p15 INK4b and p16 INK4a genes are located and frequently hypermethylated concurrently in ESCC (23).…”

Section: Discussionsupporting

confidence: 84%

DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas

et al. 2001

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The three human leukocyte antigen (HLA) class I antigens, HLA-A, HLA-B and HLA-C, play important roles in the elimination of transformed cells by cytotoxic T cells. Frequent loss of expression of these antigens at the cell surface has been observed in many human cancers. Various mechanisms for post-transcriptional regulation have been proposed and tested but the molecular mechanisms for transcriptional regulation are not clear. We show by immunohistochemistry that the HLA class I antigens are absent in 26 of 29 (89%) samples of human esophageal squamous cell carcinomas (ESCC). Eleven of the 26 ESCC samples lost mRNA expression for at least one of the HLA genes, as shown by RT-PCR. DNA from the 29 pairs of ESCC and neighboring normal epithelium were examined for CpG island hypermethylation, homozygous deletion, microsatellite instability (MSI) and loss of heterozygosity (LOH). DNA from normal epithelial tissues had no detectable methylation of the CpG islands of any of these gene loci. Thirteen of 29 ESCC samples (45%) exhibited methylation of one or more of the three HLA loci and six samples (21%) exhibited methylation of all three loci. The HLA-B gene locus was most frequently methylated (38%). HLA-B mRNA expression in an ESCC cell line, where HLA-B was hypermethylated and did not express mRNA, was activated after treatment with 5-aza-2'-deoxycytidine. Homozygous deletion of these three gene loci was not observed. Relatively low rates of LOH and MSI were observed for the microsatellite markers D6S306, D6S258, D6S273 and D6S1666, close to the HLA-A, -B and -C loci, although a high ratio of LOH was observed at a nearby locus (represented by the markers D6S1051 and D6S1560), where the tumor suppressor gene p21(Waf1) resides. A strong correlation between genetic alterations and mRNA inactivation was observed in the ESCC samples. Our results indicate that HLA class I gene expression was frequently down-regulated in ESCC at both the protein and mRNA levels and that hypermethylation of the promoter regions of the HLA-A, -B and -C genes is a major mechanism of transcriptional inactivation.

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Section: Discussionsupporting

confidence: 84%

DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas

et al. 2001

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“…The correspondence between protein and mRNA levels of HLA‐A and ‐B antigens that we found in melanoma cells and in autologous lymphoid cells, both constitutively and following exposure to IFN‐γ, suggested that transcriptional rather than post‐transcriptional mechanisms account for their level of expression on both cell types under different conditions. Consistent with this assumption, differences in the nucleotide sequences of the ISRE and its immediately flanking sites of HLA‐A and ‐B loci were found to be responsible for their constitutively unbalanced transcription5, 7, 8 and for the preferential up‐regulation of HLA‐B antigens mediated by IFN‐γ 8. Further support to the role of IFN‐γ as preferential inducer of HLA‐B antigens derives from the demonstration that, at variance with IFN‐γ, 5‐AZA‐CdR up‐regulated the expression of HLA‐A and ‐B loci to a similar extent (Table II).…”

Section: Discussionmentioning

confidence: 65%

“…Conversely, additional studies have shown that a differential regulation of the expression of HLA‐A and ‐B loci associates with malignant transformation of melanocytes, leading to a constitutively down‐regulated expression of HLA‐B antigens in melanomas and melanoma cell lines3 and most recently in uveal melanoma cell lines 4. Different mechanisms have been suggested to be responsible for this phenomenon, among these: i) high levels of the c ‐ myc oncogene or of p53 that suppress HLA‐B expression;5 ii) an increased frequency of the binding of transcriptional repressors to the interferon‐stimulated response element (ISRE) located at HLA‐B promoter;6 iii) the presence of regulatory regions, with different nucleotide sequences and binding activities between HLA‐A and ‐B loci, that mediate transcriptional repression of HLA‐B locus 7, 8. In spite of these evidences, low amounts of HLA‐B antigens have also been detected on melanocytes, suggesting that the down‐regulation of HLA‐B antigens and the mechanism(s) underlying this phenomenon are lineage‐specific properties of melanocytic cells and are not restricted to melanoma cells 9…”

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confidence: 99%

Unbalanced expression of HLA-A and -B antigens: A specific feature of cutaneous melanoma and other non-hemopoietic malignancies reverted by IFN-?

et al. 2001

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Conflicting evidences suggested that levels of HLA‐A and ‐B antigens expressed on normal and neoplastic cells of given individuals are genetically predetermined, or, on the other hand, regulated by molecular mechanisms generating the down‐regulated expression of HLA‐B antigens frequently observed on melanoma cells. In our study, we quantitated, both at the protein and mRNA level, the amounts of HLA‐A and ‐B antigens constitutively expressed on 23 primary cultures of metastatic melanomas and on autologous peripheral blood mononuclear cells (PBMC). Flow cytometric analyses identified a significantly (p < 0.01) lower expression of HLA‐B antigens on melanoma cell cultures but not on autologous PBMC. Consistently, lower amounts of HLA‐B antigens mRNA were detected by RNase protection assay exclusively in neoplastic cells. This unbalanced expression of HLA‐A and ‐B antigens was readily reverted by interferon (IFN)‐γ but not by the DNA hypomethylating agent 5‐aza‐2′‐deoxycytidine in 4 melanoma cell cultures investigated. Significantly (p < 0.05) lower levels of HLA‐B antigens were also detected on cells from solid malignancies of different histotypes but not on neoplastic cells from hemopoietic neoplasms; levels of HLA‐B antigens were rapidly up‐regulated by IFN‐γ exclusively on non‐hemopoietic transformed cells. Together, these data strongly argue against a genetic predetermination of the amounts of HLA‐A and ‐B antigens expressed on normal and neoplastic cells of distinct melanoma patients and suggest that constitutively low levels of HLA‐B antigens are a specific feature of non‐hemopoietic transformed cells that is controlled by common regulatory mechanism(s) and that is possibly shared by non‐hemopoietic normal cells. © 2001 Wiley‐Liss, Inc.

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“…Of note, following B cell activation and differentiation into plasma cells and memory cells, CXCR5 becomes down-regulated while the same effect is induced in vitro following anti-CD40 stimulation (39) and CD40L methylation appears to be altered in PBC (40). Fourth, HLA-B is also down-regulated in PBC, similar to several types of cancer (41–43). …”

Section: Discussionmentioning

confidence: 97%

Genome-Wide Analysis of DNA Methylation, Copy Number Variation, and Gene Expression in Monozygotic Twins Discordant for Primary Biliary Cirrhosis

et al. 2014

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Primary biliary cirrhosis (PBC) is an uncommon autoimmune disease with a homogeneous clinical phenotype that reflects incomplete disease concordance in monozygotic (MZ) twins. We have taken advantage of a unique collection consisting of genomic DNA and mRNA from peripheral blood cells of female MZ twins (n = 3 sets) and sisters of similar age (n = 8 pairs) discordant for disease. We performed a genome-wide study to investigate differences in (i) DNA methylation (using a custom tiled four-plex array containing tiled 50-mers 19,084 randomly chosen methylation sites), (ii) copy number variation (CNV) (with a chip including markers derived from the 1000 Genomes Project, all three HapMap phases, and recently published studies), and/or (iii) gene expression (by whole-genome expression arrays). Based on the results obtained from these three approaches we utilized quantitative PCR to compare the expression of candidate genes. Importantly, our data support consistent differences in discordant twins and siblings for the (i) methylation profiles of 60 gene regions, (ii) CNV of 10 genes, and (iii) the expression of 2 interferon-dependent genes. Quantitative PCR analysis showed that 17 of these genes are differentially expressed in discordant sibling pairs. In conclusion, we report that MZ twins and sisters discordant for PBC manifest particular epigenetic differences and highlight the value of the epigenetic study of twins.

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HLA-B down-regulation in human melanoma is mediated by sequences located downstream of the transcription-initiation site

Cited by 11 publications

References 21 publications

DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas

DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas

Unbalanced expression of HLA-A and -B antigens: A specific feature of cutaneous melanoma and other non-hemopoietic malignancies reverted by IFN-?

Genome-Wide Analysis of DNA Methylation, Copy Number Variation, and Gene Expression in Monozygotic Twins Discordant for Primary Biliary Cirrhosis

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