title: The demethylating agent 5-Aza reduces the growth, invasiveness, and clonogenicity of uveal and cutaneous melanoma.
abstract: OBJECTIVE
  Uveal melanoma is the most common primary intraocular malignancy in adults. Although local disease can be controlled with radiation therapy or enucleation, many cases are complicated by metastases, which account for the significant mortality from this disease. To date, no chemotherapeutic regimens effectively treat local or metastatic disease. Epigenetic silencing of tumor suppressor genes has been shown to be an important factor in the growth and metastasis of many cancers. One form of epigenetic alteration is DNA methylation, which often occurs at promoter elements resulting in the silencing of target gene transcription.
  
  
  METHODS
  We used 5-aza-2'-deoxycytidine (5-Aza), a well characterized demethylating agent that is US Food and Drug Administration approved to decrease DNA methylation in multiple uveal and cutaneous melanoma cell lines.
  
  
  RESULTS
  Demethylation of melanoma cell lines using 5-Aza causes significant decreases in growth, invasion, and clonogenicity. Treatment of melanoma cells with combined 5-Aza therapy and irradiation showed an even more pronounced effect on cell viability. In addition, treatment with 5-Aza decreased the number of metastases from the eye to the lung in a murine cutaneous melanoma xenograft model.
  
  
  CONCLUSIONS
  We demonstrate in vitro and in vivo that demethylating agents such as 5-Aza may be promising chemotherapeutic agents for treating melanoma and decreasing progression to metastatic disease. These results provide proof of concept for an exciting potential therapy to reduce mortality from this disease. Future work will focus on identifying pathways that mediate these changes.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Rajaii
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Asnaghi
authors.affiliation: Department of Biology, James Madison University, Harrisonburg, Virginia, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Enke
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
authors.forename: Shannath L
authors.initials: SL
authors.lastname: Merbs
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000187:drug effects*; D000077209:Decitabine; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma; D000098943:Uveal Melanoma
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine
keywords: demethylation; epigenetics; melanoma; metastasis; uveal melanoma