title: Nucleus accumbens-associated 1 contributes to cortactin deacetylation and augments the migration of melanoma cells.
abstract: We investigated the prognostic significance and post-transcriptional acetylation-modification of cortactin (CTTN) via the nucleus accumbens-associated 1 (NACC1)-histone deacetylase 6 (HDAC6) deacetylation system in primary melanomas and melanoma cell lines. Overexpression of CTTN protein was observed in 56 (73%) of 77 stage I-IV melanomas, and was significantly correlated with tumor thickness, lymph node metastasis, distant metastasis, and disease outcome. The patients whose tumors exhibited CTTN overexpression had a poorer outcome than patients without this feature (P=0.028, log-rank test). NACC1 and CTTN proteins, but not HDAC6, were overexpressed in four melanoma cell lines in comparison with a primary culture of normal human epidermal melanocytes. Knockdown of both NACC1 and HDAC6 markedly downregulated the migration activity of all melanoma cell lines (P<0.05), and induced a gain of CTTN protein acetylation status. Confocal microscopy showed that hyperacetylation of CTTN modulated by depletion of both NACC1 and HDAC6 induced disappearance of CTTN protein at the leading edge of migrating cells, resulting in stabilization of the focal adhesion structure and development of actin stress fibers. These data suggest that the acetylation status of CTTN modulated by the NACC1-HDAC6 deacetylation system induces acceleration of melanoma cell migration activity via an actin-dependent cellular process, possibly contributing to aggressive behavior (invasion/metastasis) of the melanoma cells.
authors.affiliation: Division of Bioscience, Department of Tumor Biology, Center for Advanced Medical Science, Morioka, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Tsunoda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tatemichi
authors.forename: Sosuke
authors.initials: S
authors.lastname: Muraoka
authors.forename: Shinpei
authors.initials: S
authors.lastname: Miura
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shibazaki
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Maeda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Toshihide
authors.initials: T
authors.lastname: Akasaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Masuda
authors.forename: Chihaya
authors.initials: C
authors.lastname: Maesawa
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D022502:Stress Fibers / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C495868:CTTN protein, human; D051356:Cortactin; C516477:NACC1 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases