title: Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway.
abstract: Deltex-3-like (DTX3L), an E3 ligase, is a member of the Deltex (DTX) family and is also called B-lymphoma and BAL-associated protein (BBAP). Previously, we established RFP/RET-transgenic mice, in which systemic hyperpigmented skin, benign melanocytic tumor(s) and melanoma(s) develop stepwise. Here we showed that levels of Dtx3l/DTX3L in spontaneous melanoma in RFP/RET-transgenic mice and human melanoma cell lines were significantly higher than those in benign melanocytic cells and primarily cultured normal human epithelial melanocytes, respectively. Immunohistochemical analysis of human tissues showed that more than 80% of the melanomas highly expressed DTX3L. Activity of FAK/PI3K/AKT signaling, but not that of MEK/ERK signaling, was decreased in Dtx3l/DTX3L-depleted murine and human melanoma cells. In summary, we demonstrated not only increased DTX3L level in melanoma cells but also DTX3L-mediated regulation of invasion and metastasis in melanoma through FAK/PI3K/AKT but not MEK/ERK signaling. Our analysis in human BRAFV600E inhibitor-resistant melanoma cells showed about 80% decreased invasion in the DTX3L-depleted cells compared to that in the DTX3L-intact cells. Thus, DTX3L is clinically a potential therapeutic target as well as a potential biomarker for melanoma.
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.|Department of Biochemistry and Plant Physiology, VNU University of Science, Vietnam National University, Hanoi, Vietnam.
authors.forename: Nguyen Dinh
authors.initials: ND
authors.lastname: Thang
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.|Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yajima
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.|Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Mayuko Y
authors.initials: MY
authors.lastname: Kumasaka
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.|Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Machiko
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.|Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C475669:DTX3L protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Deltex-3-like; FAK/PI3K/AKT pathway; cancer; melanoma; metastasis