title: DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition.
abstract: Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1(-/-) and Dear1(+/-) mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGF-β results in failure of acinar morphogenesis, upregulation of epithelial-mesenchymal transition (EMT) markers, anoikis resistance, migration, and invasion. Furthermore, DEAR1 blocks TGF-β-SMAD3 signaling, resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGF-β-induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors SNAIL1 and SNAIL2, with genetic alteration of DEAR1/SNAIL2 serving as prognostic markers of overall poor survival in a cohort of 889 cases of invasive breast cancer.
  
  
  CONCLUSIONS
  Cumulative results provide compelling evidence that DEAR1 is a critical tumor suppressor involved in multiple human cancers and provide a novel paradigm for regulation of TGF-β-induced EMT through DEAR1's regulation of SMAD3 protein levels. DEAR1 loss of function has important therapeutic implications for targeted therapies aimed at the TGF-β-SMAD3 pathway.
authors.affiliation: Departments of 1Genetics and, 2Hematopathology, 3Pathology,4Translational Molecular Pathology, and 5Epidemiology, The University of Texas MD Anderson Cancer Center; 6The Human and Molecular Genetics Program, The University of Texas, Graduate School of Biomedical Science at Houston, Houston, Texas.
authors.forename: Nanyue
authors.initials: N
authors.lastname: Chen
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Balasenthil
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Reuther
authors.forename: Aileen
authors.initials: A
authors.lastname: Frayna
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Chandler
authors.forename: Lynne V
authors.initials: LV
authors.lastname: Abruzzo
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Erica
authors.initials: E
authors.lastname: Lokken
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
authors.forename: Steven T
authors.initials: ST
authors.lastname: Lott
authors.forename: Ann McNeill
authors.initials: AM
authors.lastname: Killary
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D011379:Prognosis; D011945:Receptors, Angiotensin / Q000235:genetics*; D017466:Receptors, Endothelin / Q000235:genetics*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D014408:Biomarkers, Tumor; C510877:Dear1 protein, mouse; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; C000604407:SNAI1 protein, human; D051900:Smad3 Protein; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; C583162:TRIM62 protein, human; D044767:Ubiquitin-Protein Ligases