American Association for Cancer Research
21598290cd120499-sup-supp_video_3.mp4 (3.27 MB)

Video 3 from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition

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posted on 2023-04-03, 20:20 authored by Nanyue Chen, Seetharaman Balasenthil, Jacquelyn Reuther, Aileen Frayna, Ying Wang, Dawn S. Chandler, Lynne V. Abruzzo, Asif Rashid, Jaime Rodriguez, Guillermina Lozano, Yu Cao, Erica Lokken, Jinyun Chen, Marsha L. Frazier, Aysegul A. Sahin, Ignacio I. Wistuba, Subrata Sen, Steven T. Lott, Ann McNeill Killary

Video 3 - MP4 file 3352K, DEAR1-shRNA clone without TGF-beta



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.Significance: 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. Cancer Discov; 3(10); 1172–89. ©2013 AACR.This article is highlighted in the In This Issue feature, p. 1083

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