Epac increases melanoma cell migration by a heparan sulfate-related mechanism.
Melanoma, the most malignant form of human skin cancer, has a poor prognosis due to its strong metastatic ability. It was recently demonstrated that Epac, an effector molecule of cAMP, is involved in regulating cell migration; however, the role of Epac in melanoma cell migration remains unclear. We thus examined whether Epac regulates cell migration and metastasis of melanoma. Epac activation, by either specific agonist or overexpression of Epac, increased melanoma cell migration. Deletion of endogenous Epac with small interfering RNA decreased basal melanoma cell migration. These data suggested a major role of Epac in melanoma cell migration. Epac-induced cell migration was mediated by translocation of syndecan-2, a cell-surface heparan sulfate proteoglycan, to lipid rafts. This syndecan-2 translocation was regulated by tubulin polymerization via the Epac/phosphoinositol-3 kinase pathway. Epac-induced cell migration was also regulated by the production of heparan sulfate, a major extracellular matrix. Epac-induced heparan sulfate production was attributable to the increased expression of N-deacetylase/N-sulfotransferase-1 (NDST-1) accompanied by an increased NDST-1 translation rate. Finally, Epac overexpression enhanced lung colonization of melanoma cells in mice. Taken together, these data indicate that Epac regulates melanoma cell migration/metastasis mostly via syndecan-2 translocation and heparan sulfate production.
Baljinnyam
Erdene
E
Department of Cell Biology and Molecular Medicine, New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
Iwatsubo
Kousaku
K
Kurotani
Reiko
R
Wang
Xu
X
Ulucan
Coskun
C
Iwatsubo
Mizuka
M
Lagunoff
David
D
Ishikawa
Yoshihiro
Y
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D006497:Heparan Sulfate / Q000096:biosynthesis*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D021381:Protein Transport; D015398:Signal Transduction; D015238:Sulfotransferases / Q000378:metabolism*; D053669:Syndecan-2 / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D006497:Heparan Sulfate; D019869:Phosphatidylinositol 3-Kinases; D015238:Sulfotransferases; D053669:Syndecan-2; D014404:Tubulin; C116122:RAPGEF3 protein, human; C021350:heparitin sulfotransferase