Tumor antigen PRAME is up-regulated by MZF1 in cooperation with DNA hypomethylation in melanoma cells

• Published in: Cancer letters 2017-09, Vol.403, p.144-151
• Main Authors: Lee, Yong-Kyu, Park, Ui-Hyun, Kim, Eun-Joo, Hwang, Jin-Taek, Jeong, Ji-Cheon, Um, Soo-Jong
• Format: Article
• Language: English
• Subjects: Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Binding Sites; Biotechnology; Breast cancer; Cell cycle; Cell Proliferation; Cooperation; CpG Islands; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - drug effects; DNA Modification Methylases - antagonists & inhibitors; DNA Modification Methylases - metabolism; Ectopic expression; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - drug effects; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Genes; HCT116 Cells; Hematology, Oncology and Palliative Medicine; Humans; Infections; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Leukemia; Medical prognosis; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; MZF1; PRAME; Promoter Regions, Genetic; Protein Binding; RNA Interference; Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Transcription factors; Transcription, Genetic; Transfection; Tumors; Up-Regulation; Zinc; Zinc finger proteins
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.06.015

Abstract Elevated expression of preferentially expressed antigen in melanoma (PRAME) has been implicated in disease progression in a variety of cancers. However, the mechanisms underlying the transcriptional regulation of PRAME remain largely unexplored. Initially, we observed that PRAME was elevated in proportion to the malignant potential of melanoma cells. From the in silico prediction of PRAME gene structure, we identified the putative myeloid zinc finger 1 (MZF1) binding sites, which overlap with a CpG-rich region located in the first intron. The transcription factor MZF1 increased PRAME expression via its direct binding to the intron DNA. Upon treatment with a DNA methylation inhibitor, 5-aza-2’-deoxycitidine (5-azaC), together with ectopic expression of MZF1, PRAME expression was significantly enhanced at both the protein and mRNA levels. More pronounced MZF1 binding to the PRAME DNA was observed in the presence of 5-azaC. DNA methylation was inversely correlated with PRAME expression in melanoma cells. Finally, we observed that MZF1, like PRAME, promotes the colony-forming ability in melanoma cells. Overall, our findings suggest that MZF1, via stimulation of PRAME expression, may be a potential prognostic and therapeutic target in melanoma.