TY - JOUR
T1 - Dear1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition
AU - Chen, Nanyue
AU - Balasenthil, Seetharaman
AU - Reuther, Jacquelyn
AU - Frayna, Aileen
AU - Wang, Ying
AU - Chandler, Dawn S.
AU - Abruzzo, Lynne V.
AU - Rashid, Asif
AU - Rodriguez, Jaime
AU - Lozano, Guillermina
AU - Cao, Yu
AU - Lokken, Erica
AU - Chen, Jinyun
AU - Frazier, Marsha L.
AU - Sahin, Aysegul A.
AU - Wistuba, Ignacio I.
AU - Sen, Subrata
AU - Lott, Steven T.
AU - Killary, Ann Mc Neill
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-12-0499
DO - 10.1158/2159-8290.CD-12-0499
M3 - Article
C2 - 23838884
AN - SCOPUS:84885612989
SN - 2159-8274
VL - 3
SP - 1172
EP - 1189
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -