title: RASSF1A suppresses melanoma development by modulating apoptosis and cell-cycle progression.
abstract: The tumor suppressor candidate gene Ras association domain family 1, isoform A (RASSF1A) encodes a microtubule-associated protein that is implicated in the regulation of cell proliferation, migration, and apoptosis. Several studies indicate that down-regulation of RASSF1A resulting from promoter hypermethylation is a frequent epigenetic abnormality in malignant melanoma. In this study, we report that compared with melanocytes in normal skins or benign skin lesions, RASSF1A is down-regulated in melanoma tissues as well as cell lines, and its expression negatively correlates with lymph node metastasis. Following ectopic expression in RASSF1A-deficient melanoma A375 cell line, RASSF1A reduces cell viability, suppresses cell-cycle progression but enhances apoptotic cell death. In vivo, RASSF1A expression inhibits the tumorigenic potential of A375 cells in nude mice, which also correlates with decreased cell proliferation and increased apoptosis. On the molecular level, ectopic RASSF1A expression leads to differential expression of 209 genes, including 26 down-regulated and 183 up-regulated ones. Among different signaling pathways, activation of the apoptosis signal-regulating kinase 1 (ASK1)/p38 MAP kinase signaling is essential for RASSF1A-induced mitochondrial apoptosis, and the inhibition of the Akt/p70S6 kinase/eIF4E signaling is also important for RASSF1A-mediated apoptosis and cell-cycle arrest. This is the first study exploring the biological functions and the underlying mechanisms of RASSF1A during melanoma development. It also identifies potential targets for further diagnosis and clinical therapy.
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yi
authors.forename: Jianbo
authors.initials: J
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.forename: Xiayu
authors.initials: X
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Yixin
authors.initials: Y
authors.lastname: Tan
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: James B
authors.initials: JB
authors.lastname: McCarthy
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Xiang
authors.forename: Hongfu
authors.initials: H
authors.lastname: Xie
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human