A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

• DOI: 10.1038/ncomms9093
• Publication Date: 2015-08-26T10:27:09Z
• Authors: Alejandro Conde-P...; Gwendoline Gros; Christine Longvert; Malin Pedersen; Valérie Petit; Zackie Aktary; Amaya Viros; Franck Gesbert; Véronique Delmas; Florian Rambow; Boris C. Bastian; Andrew D. Campbell; Sophie Colombo; Isabel Puig; Alfonso Bellacosa; Owen Sansom; Richard Marais; Leon C. L. T. Van...; Lionel Larue
• Keywords: 0301 basic medicine; Skin Neoplasms; Caveolin 1; Transgenic; GTP Phosphohydrolases; Glycogen Synthase Kinase 3; Mice; Phosphatidylinositol 3-Kinases; 2.1 Biological and endogenous factors; Aetiology; Melanoma; beta Catenin; Cancer; Feedback, Physiological; Microscopy; 0303 health sciences; Tumor; Blotting; Biological Sciences; Prognosis; Cadherins; Immunohistochemistry; 3. Good health; Melanocytes; Western; Transcriptional Activation; 570; Physiological; Blotting, Western; 610; Mice, Transgenic; 612; Fluorescence; Article; Cell Line; Feedback; 03 medical and health sciences; Cell Line, Tumor; Genetics; Animals; Humans; Glycogen Synthase Kinase 3 beta; Biomedical and Clinical Sciences; PTEN Phosphohydrolase; Membrane Proteins; ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre; MicroRNAs; Microscopy, Fluorescence; Biochemistry and Cell Biology; PRIMARY CUTANEOUS MELANOMA TUMOR-SUPPRESSOR GENE METASTATIC MELANOMA CELL-MIGRATION CANCER CELLS ACTIVATION SENESCENCE EXPRESSION PROLIFERATION INVASION; Proto-Oncogene Proteins c-akt

AbstractLoss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K–AKT–GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRASQ61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β–catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.