title: Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors.
abstract: Epigenetic mechanisms influence molecular patterns important for the bone-metastatic process, and here we highlight the role of WW-domain containing oxidoreductase (Wwox). The tumor-suppressor Wwox lacks in almost all cancer types; the variable expression in osteosarcomas is related to lung-metastasis formation, and exogenous Wwox destabilizes HIF-1α (subunit of Hypoxia inducible Factor-1, HIF-1) affecting aerobic glycolysis. Our recent studies show critical functions of Wwox present in 1833-osteotropic clone, in the corresponding xenograft model, and in human bone metastasis from breast carcinoma. In hypoxic-bone metastatic cells, Wwox enhances HIF-1α stabilization, phosphorylation, and nuclear translocation. Consistently, in bone-metastasis specimens Wwox localizes in cytosolic/perinuclear area, while TAZ (transcriptional co-activator with PDZ-binding motif) and HIF-1α co-localize in nuclei, playing specific regulatory mechanisms: TAZ is a co-factor of HIF-1, and Wwox regulates HIF-1 activity by controlling HIF-1α. In vitro, DNA methylation affects Wwox-protein synthesis; hypoxia decreases Wwox-protein level; hepatocyte growth factor (HGF) phosphorylates Wwox driving its nuclear shuttle, and counteracting a Twist program important for the epithelial phenotype and metastasis colonization. In agreement, in 1833-xenograft mice under DNA-methyltransferase blockade with decitabine, Wwox increases in nuclei/cytosol counteracting bone metastasis with prolongation of the survival. However, Wwox seems relevant for the autophagic process which sustains metastasis, enhancing more Beclin-1 than p62 protein levels, and p62 accumulates under decitabine consistent with adaptability of metastasis to therapy. In conclusion, Wwox methylation as a bone-metastasis therapeutic target would depend on autophagy conditions, and epigenetic mechanisms regulating Wwox may influence the phenotype of bone metastasis.
authors.affiliation: Galeazzi Orthopaedic Institute, Scientific Institute for Research, Hospitalization and Health Care (IRCCS), 20161 Milano, Italy. paola.maroni@grupposandonato.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Maroni
authors.affiliation: Department of Biomedical Sciences for Health, Molecular Pathology Laboratory, Università degli Studi di Milano, 20133 Milano, Italy. emanuela.matteucci@unimi.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Matteucci
authors.affiliation: Department of Biomedical Sciences for Health, Molecular Pathology Laboratory, Università degli Studi di Milano, 20133 Milano, Italy. paola.bendinelli@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Bendinelli
authors.affiliation: Department of Biomedical Sciences for Health, Molecular Pathology Laboratory, Università degli Studi di Milano, 20133 Milano, Italy. a.desiderio@unimi.it.
authors.forename: Maria Alfonsina
authors.initials: MA
authors.lastname: Desiderio
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Wwox; bone metastasis; epigenetic reprogramming; transcription factors