Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway

Nguyen Dinh Thang, Ichiro Yajima, Mayuko Y. Kumasaka, Machiko Iida, Tamio Suzuki, Masashi Kato

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 inhibitorresistant 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.

Original languageEnglish
Pages (from-to)14290-14299
Number of pages10
JournalOncotarget
Volume6
Issue number16
Publication statusPublished - 2015 Jan 1
Externally publishedYes

Keywords

  • Cancer
  • Deltex-3-like
  • FAK/PI3K/AKT pathway
  • Melanoma
  • Metastasis

ASJC Scopus subject areas

  • Oncology

Cite this

Thang, N. D., Yajima, I., Kumasaka, M. Y., Iida, M., Suzuki, T., & Kato, M. (2015). Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. Oncotarget, 6(16), 14290-14299.

Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. / Thang, Nguyen Dinh; Yajima, Ichiro; Kumasaka, Mayuko Y.; Iida, Machiko; Suzuki, Tamio; Kato, Masashi.

In: Oncotarget, Vol. 6, No. 16, 01.01.2015, p. 14290-14299.

Research output: Contribution to journalArticle

Thang, ND, Yajima, I, Kumasaka, MY, Iida, M, Suzuki, T & Kato, M 2015, 'Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway', Oncotarget, vol. 6, no. 16, pp. 14290-14299.
Thang ND, Yajima I, Kumasaka MY, Iida M, Suzuki T, Kato M. Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. Oncotarget. 2015 Jan 1;6(16):14290-14299.
Thang, Nguyen Dinh ; Yajima, Ichiro ; Kumasaka, Mayuko Y. ; Iida, Machiko ; Suzuki, Tamio ; Kato, Masashi. / Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. In: Oncotarget. 2015 ; Vol. 6, No. 16. pp. 14290-14299.
@article{da98d4032d254693bf0b8adedb64569a,
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 inhibitorresistant 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.",
keywords = "Cancer, Deltex-3-like, FAK/PI3K/AKT pathway, Melanoma, Metastasis",
author = "Thang, {Nguyen Dinh} and Ichiro Yajima and Kumasaka, {Mayuko Y.} and Machiko Iida and Tamio Suzuki and Masashi Kato",
year = "2015",
month = "1",
day = "1",
language = "English",
volume = "6",
pages = "14290--14299",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "16",

}

TY - JOUR

T1 - Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway

AU - Thang, Nguyen Dinh

AU - Yajima, Ichiro

AU - Kumasaka, Mayuko Y.

AU - Iida, Machiko

AU - Suzuki, Tamio

AU - Kato, Masashi

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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 inhibitorresistant 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.

AB - 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 inhibitorresistant 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.

KW - Cancer

KW - Deltex-3-like

KW - FAK/PI3K/AKT pathway

KW - Melanoma

KW - Metastasis

UR - http://www.scopus.com/inward/record.url?scp=84931053474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931053474&partnerID=8YFLogxK

M3 - Article

VL - 6

SP - 14290

EP - 14299

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 16

ER -