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Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells

Oncogene volume 25, pages 2873–2884 (2006)Cite this article

Abstract

The human high molecular weight-melanoma associated antigen (HMW-MAA) is a membrane-bound chondroitin sulfate proteoglycan that is variably expressed in a high percentage of melanoma cell lines and tumors. Since the mechanism(s) regulating HMW-MAA expression has(ve) not been defined, in this study, we have examined whether promoter DNA methylation regulates the level of HMW-MAA expression. In melanoma cell lines, the level of HMW-MAA mRNA and protein expression is coordinately regulated, implicating a transcriptional control mechanism. Consistent with a role for regulation by DNA methylation, we have found that a dense CpG island flanks the human HMW-MAA gene transcriptional start site. Methylation-specific PCR and sodium bisulfite DNA sequencing analyses indicate that the HMW-MAA promoter is heavily methylated in melanoma cell lines, melanoma lesions and normal lymphocytes that do not express HMW-MAA; in contrast, the HMW-MAA promoter is not methylated in melanoma cell lines and tumors that express this antigen. In addition, HMW-MAA expression is markedly induced in HMW-MAA-negative melanoma cell lines by incubation with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. In summary, our results establish DNA methylation as a key regulator of HMW-MAA expression by human melanoma cells. This information represents a useful background to optimize immunotherapeutic strategies targeting HMW-MAA.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ALM:

acral lentiginous melanoma

Anti-id:

anti-idiotypic

BSA:

bovine serum albumin

DAC:

5-aza-2′-deoxycytidine

ERK1/2:

extracellular signal-regulated protein kinases 1 and 2

FAK:

focal adhesion kinase

HMW-MAA:

high molecular weight-melanoma associated antigen

IHC:

immunohistochemical

LMM:

lentigo maligna melanoma

mAb:

monoclonal antibody

MSP:

methylation-specific polymerase chain reaction

qRT-PCR:

quantitative real-time PCR

RT-PCR:

reverse transcription-PCR

SSM:

superficial spreading melanomas

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Acknowledgements

This work was supported by PHS Grants P01 CA89480 and R01 CA105500 awarded by the National Cancer Institute, and by a grant from the Harry J Lloyd Charitable Trust (to SF). ARK acknowledges generous support from the Ralph Wilson Medical Research Foundation, the Roswell Park Alliance Foundation, and the Phi Beta Psi Sorority. We thank Smitha James and Petra Link of the Karpf laboratory for expert technical assistance. We also thank our many collaborators for providing the human melanoma cell lines used in this study.

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Authors and Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

    W Luo, X Wang & S Ferrone

  2. Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

    A R Karpf

  3. Department of Dermatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    T Kageshita & S Wakasugi

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  1. W Luo
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  2. X Wang
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Correspondence to S Ferrone.

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Luo, W., Wang, X., Kageshita, T. et al. Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells. Oncogene 25, 2873–2884 (2006). https://doi.org/10.1038/sj.onc.1209319

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