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Int. J. Mol. Sci. 2017, 18(1), 75; doi:10.3390/ijms18010075

Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors

1
Galeazzi Orthopaedic Institute, Scientific Institute for Research, Hospitalization and Health Care (IRCCS), 20161 Milano, Italy
2
Department of Biomedical Sciences for Health, Molecular Pathology Laboratory, Università degli Studi di Milano, 20133 Milano, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Nicoletta Sacchi
Received: 14 September 2016 / Revised: 26 October 2016 / Accepted: 24 November 2016 / Published: 1 January 2017
(This article belongs to the Special Issue Cancer Epigenetics)
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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. View Full-Text
Keywords: bone metastasis; epigenetic reprogramming; Wwox; transcription factors bone metastasis; epigenetic reprogramming; Wwox; transcription factors
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Maroni, P.; Matteucci, E.; Bendinelli, P.; Desiderio, M.A. Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors. Int. J. Mol. Sci. 2017, 18, 75.

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