title: Oxidative DNA damage induces the ATM-mediated transcriptional suppression of the Wnt inhibitor WIF-1 in systemic sclerosis and fibrosis.
abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by extensive visceral organ and skin fibrosis. SSc patients have increased production of autoreactive antibodies and Wnt signaling activity. We found that expression of the gene encoding Wnt inhibitor factor 1 (WIF-1) was decreased in fibroblasts from SSc patient biopsies. WIF-1 deficiency in SSc patient cells correlated with increased abundance of the Wnt effector β-catenin and the production of collagen. Knocking down WIF-1 in normal fibroblasts increased Wnt signaling and collagen production. WIF-1 loss and DNA damage were induced in normal fibroblasts by either SSc patient immunoglobulins or oxidative DNA-damaging agents, such as ultraviolet light, hydrogen peroxide, or bleomycin. The DNA damage checkpoint kinase ataxia telangiectasia mutated (ATM) mediated WIF-1 silencing through the phosphorylation of the transcription factor c-Jun, which in turn activated the expression of the gene encoding activating transcription factor 3 (ATF3). ATF3 and c-Jun were recruited together with histone deacetylase 3 (HDAC3) to the WIF-1 promoter and inhibited WIF-1 expression. Preventing the accumulation of reactive oxygen species or inhibiting the activation of ATM, c-Jun, or HDACs restored WIF-1 expression in cultured SSc patient cells. Trichostatin A, an HDAC inhibitor, prevented WIF-1 loss, β-catenin induction, and collagen accumulation in an experimental fibrosis model. Our findings suggest that oxidative DNA damage induced by SSc autoreactive antibodies enables Wnt activation that contributes to fibrosis.
authors.affiliation: Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, 60126 Ancona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Svegliati
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di napoli Federico II, 80132 Naples, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Marrone
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di napoli Federico II, 80132 Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pezone
authors.affiliation: Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, 60126 Ancona, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Spadoni
authors.affiliation: Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, 60126 Ancona, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Grieco
authors.affiliation: Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, 60126 Ancona, Italy. Dipartimento di Medicina Interna, Ospedali Riuniti, 60126 Ancona, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Moroncini
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di napoli Federico II, 80132 Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Grieco
authors.affiliation: Cancer Research UK, Clare Hall, London EN6 3LD, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di napoli Federico II, 80132 Naples, Italy.
authors.forename: Savina
authors.initials: S
authors.lastname: Agnese
authors.affiliation: Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
authors.affiliation: Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.affiliation: Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Arcavacata di Rende (CS) 87036, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Musti
authors.affiliation: Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, 60126 Ancona, Italy. Dipartimento di Medicina Interna, Ospedali Riuniti, 60126 Ancona, Italy. avvedim@unina.it a.gabrielli@univpm.it.
authors.forename: Armando
authors.initials: A
authors.lastname: Gabrielli
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di napoli Federico II, 80132 Naples, Italy. avvedim@unina.it a.gabrielli@univpm.it.
authors.forename: Enrico V
authors.initials: EV
authors.lastname: Avvedimento
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001706:Biopsy; D001761:Bleomycin / Q000737:chemistry; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004249:DNA Damage; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D020868:Gene Silencing; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011500:Protein Synthesis Inhibitors / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D006877:Hydroxamic Acids; D007074:Immunoglobulin G; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins; D001761:Bleomycin; C012589:trichostatin A; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D010100:Oxygen