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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.

SUBMITTER: Yi M

PROVIDER: S-EPMC3081399 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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RASSF1A suppresses melanoma development by modulating apoptosis and cell-cycle progression.

Yi Mei M Yang Jianbo J Chen Xiang X Li Ji J Li Xiayu X Wang Li L Tan Yixin Y Xiong Wei W Zhou Ming M McCarthy James B JB Li Guiyuan G Xiang Bo B Xie Hongfu H

Journal of cellular physiology 20110901 9

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 m ...[more]

PMID: 21660959

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Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is the most lethal renal cancer. An overwhelming increase of patients experience tumor progression and unfavorable prognosis. However, the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear. Therefore, uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC. In this study, we sought to investigate the role of mitofusin-2 (MFN2) in supressing ccRCC tumorigenesis and metastasis.MethodsThe expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort. Both in vitro and in vivo experiments, including cell proliferation, xenograft mouse models and transgenic mouse model, were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC. RNA-sequencing, mass spectrum analysis, co-immunoprecipitation, bio-layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor-supressing role of MFN2.Resultswe reported a tumor-suppressing pathway in ccRCC, characterized by mitochondria-dependent inactivation of epidermal growth factor receptor (EGFR) signaling. This process was mediated by the outer mitochondrial membrane (OMM) protein MFN2. MFN2 was down-regulated in ccRCC and associated with favorable prognosis of ccRCC patients. in vivo and in vitro assays demonstrated that MFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway. In a kidney-specific knockout mouse model, loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney. Mechanistically, MFN2 preferably binded small GTPase Rab21 in its GTP-loading form, which was colocalized with endocytosed EGFR in ccRCC cells. Through this EGFR-Rab21-MFN2 interaction, endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM-residing tyrosine-protein phosphatase receptor type J (PTPRJ).ConclusionsOur findings uncover an important non-canonical mitochondria-dependent pathway regulating EGFR signaling by the Rab21-MFN2-PTPRJ axis, which contributes to the development of novel therapeutic strategies for ccRCC.

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RASSF1A suppresses melanoma development by modulating apoptosis and cell-cycle progression.

Publications

RASSF1A suppresses melanoma development by modulating apoptosis and cell-cycle progression.

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