Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway
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Nguyen Dinh Thang1,2, Ichiro Yajima1,3, Mayuko Y. Kumasaka1,3, Machiko Iida1,3, Tamio Suzuki4, Masashi Kato1,3
1Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
2Department of Biochemistry and Plant Physiology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
3Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
4Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
Masashi Kato, e-mail: [email protected]
Keywords: Deltex-3-like, melanoma, metastasis, cancer, FAK/PI3K/AKT pathway
Received: January 28, 2015 Accepted: April 08, 2015 Published: April 20, 2015
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.
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