Nucleus Accumbens-Associated 1 Contributes to Cortactin Deacetylation and Augments the Migration of Melanoma Cells

Tsunoda, Kenji; Oikawa, Hiroki; Tada, Hiroshi; Tatemichi, Yoshinori; Muraoka, Sosuke; Miura, Shunsuke; Shibazaki, Masahiko; Maeda, Fumihiko; Takahashi, Kazuhiro; Akasaka, Toshihide; Masuda, Tomoyuki; Maesawa, Chihaya

doi:10.1038/jid.2011.110

Cited by 23 publications

(32 citation statements)

References 43 publications

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“…We recently reported that disruption of HDAC6 was closely associated with a decease of in vitro migration and invasion activities of melanoma cells (22). Inactivation of HDAC6 induced hyperacetylation of not only TUBA1 (13) but also CTTN (22). It introduced stabilization of MT dynamicity, and prevented the translocation of cortactin protein to the cell periphery, thus blocking its association with F-actin, and impairing the motility of melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…We also recently demonstrated that the deacetylation system of nucleus accumbens-associated 1 (NACC1) and HDAC6 can modulate the status of both TUBA1 and cortactin (CTTN), which is an actin-crosslinking protein (22). Motility of melanoma cells was affected via MT-and actin-dependent processes through the NACC1/HDAC6 deacetylation system.…”

Section: Introductionmentioning

confidence: 99%

“…Motility of melanoma cells was affected via MT-and actin-dependent processes through the NACC1/HDAC6 deacetylation system. Moreover, overexpression of HDAC6 is a good prognostic and metastatic biomarker in human melanomas (22). The aggressiveness of malignant melanoma is characterized by high metastatic ability and resistance to chemotherapy and immunotherapy (23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of cylindromatosis gene, CYLD, confers a growth advantage on malignant melanoma cells while negatively regulating their migration activity

et al. 2012

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Abstract. The cylindromatosis gene (CYLD) encodes a deubiquitinase that was initially identified as a tumor suppressor and has recently been investigated in connection with a variety of normal physiological processes. In contrast to its cell-proliferative activity, the effect of CYLD protein on cell migration has been a matter of debate. We investigated the effect of CYLD-siRNA on the migration activity of malignant melanoma cells. Expression of CYLD mRNA/protein was lower in 6 of 8 malignant melanoma cell lines than in 3 sets of primarycultured normal human epidermal melanocytes. Knockdown of CYLD significantly increased the proliferation activities of two melanoma cell lines (p<0.05), along with BCL3 nuclear translocation followed by CCND1 overexpression. In contrast to the proliferation-related activity, CYLD knockdown significantly decreased the cell migration of all the melanoma cell lines (n=7, p<0.05), and we demonstrated that the mechanism regulating melanoma cell migration was activation of RAC1 through the action of CYLD. Our findings provide new insight into the role of CYLD-induced RAC1 activation in melanoma cell migration. IntroductionCYLD (cylindromatosis) was originally identified as a tumor suppressor gene that is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomal-dominant predisposition to multiple tumors of skin appendages (1). The CYLD gene encodes a deubiquitinating enzyme, which removes lysine 48-or lysine 63-linked polyubiquitin chains from target proteins (2). Depending on the cellular context, CYLD has been shown to negatively regulate the NF-κB and/or JNK-signaling pathways resulting in suppression of cell proliferation and survival (3-6).The mechanism by which CYLD exerts its tumor-suppressor function in vivo has been analyzed in CYLD-null mice, which are highly susceptible to chemically-induced skin tumors. This increased tumor incidence has been attributed to loss of an inhibitory interaction between CYLD and the proto-oncogene BCL3. The association of CYLD with BCL3, which results from activation and subsequent perinuclear translocation of the protein, leads to the removal of a lysine 63-linked ubiquitin chain from BCL3, which in turn inhibits the nuclear translocation and activity of BCL3 (7). In the absence of CYLD gene expression, BCL3 is able to translocate into the nucleus where it forms a complex with the NF-κB p50 and p52 isoforms. This results in activation of the cyclin D1 (CCND1) promoter and increased proliferation and tumor growth (7).In contrast to the proliferation activity of tumor cells, the effect of CYLD protein in cell migration has been a matter of debate. Some CYLD mutants mimicking mutations that have been identified in human cylindromatosis contribute to the acquisition of metastatic potential by tumor cells (8-10). However, Gao et al (11,12) have demonstrated that CYLD downregulation causes a decrease of cell migration activity in both cancer and endothelial cells. The CYLD gene is known to contain 3 cytoskeleton-associated protein g...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Downregulation of cylindromatosis gene, CYLD, confers a growth advantage on malignant melanoma cells while negatively regulating their migration activity

et al. 2012

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“…In contrast, only five karyometric features descriptive of the nuclear chromatin distribution provided a recognition of more than 70% of patients who might benefit from intensive therapy. The karyometric features relate to subtle changes in the spatial and statistical distribution of the nuclear chromatin, suggesting not only histone modification but also cellular aggression [20].…”

Section: Discussionmentioning

confidence: 99%

Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases

et al. 2016

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This small exploratory study was designed to test the hypothesis that thin melanoma lesions contain nuclei of two similar phenotypes, in different proportions. In lesions likely to progress to metastatic disease, one of these phenotypes predominates. Histopathological sections from 18 cases of thin melanomas which did not progress to metastasis, and from 10 cases which did progress were imaged and digitized at high resolution, with a total of 2084 and 1148 nuclei, respectively, recorded. Five karyometric features were used to discriminate between nuclei from indolent and from potentially metastatic lesions. For each case, the percentage of nuclei classified by the discriminant function as having come from a potentially metastatic lesion was determined and termed as case classification criterion. Standard histopathological criteria, such as ulceration and high mitotic index, indicated in this material the need for intensive therapy for only one of the 10 participants, as compared with 7/10 identified correctly by the karyometric measure. Using a case classification criterion threshold of 40%, the overall accuracy was 86% in the test set. The proportion of nuclei of an aggressive phenotype may lend itself as an effective prognostic clue for thin melanoma lesions. The algorithm developed in this training set appears to identify those patients at high risk for metastatic disease, and demonstrates a basis for a further study to assess the utility of prognostic clues for thin melanomas.

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MiRNA‐545 negatively regulates the oncogenic activity of EMS1 in gastric cancer

Zhao

et al. 2018

Cancer Medicine

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Gastric cancer (GC) is a common malignant tumor of the digestive system. In addition, GC metastasis is an extremely complicated process. In this article, high expression levels of EMS1 mRNA and protein were found to be positively correlated with an enhanced malignant potential of GC cells and a poor clinical prognosis of GC patients. Interestingly, the expression levels of EMS1 mRNA and protein in GC cells were inhibited by microRNA‐545 (miR‐545), which was identified by a bioinformatics analysis. The expression level of miR‐545 in carcinoma tissues was significantly lower than that in para‐carcinoma tissues. The proliferation and epithelial‐mesenchymal transition (EMT) of GC cells were suppressed by exogenous oligonucleotides of miR‐545 mimics. In addition, the expression levels of EMT‐associated markers were altered with the expression of miR‐545. Notably, the growth rates of tumors in nude mice were seriously restrained by an intratumoral injection of oligonucleotides of the miR‐545 mimics. These results suggest a negative regulatory role of miR‐545 on the oncogenic activity of EMS1. In addition, EMS1 and miR‐545 may be potential biomarkers for GC diagnosis. Synthesized oligonucleotides of miR‐545 mimics may be developed as important gene medicines for GC therapy in the future.

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Nucleus Accumbens-Associated 1 Contributes to Cortactin Deacetylation and Augments the Migration of Melanoma Cells

Cited by 23 publications

References 43 publications

Downregulation of cylindromatosis gene, CYLD, confers a growth advantage on malignant melanoma cells while negatively regulating their migration activity

Downregulation of cylindromatosis gene, CYLD, confers a growth advantage on malignant melanoma cells while negatively regulating their migration activity

Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases

MiRNA‐545 negatively regulates the oncogenic activity of EMS1 in gastric cancer

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