TY - JOUR
T1 - CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling
AU - Ying, Zhe
AU - Tian, Han
AU - Li, Yun
AU - Lian, Rong
AU - Li, Wei
AU - Wu, Shanshan
AU - Zhang, Hui Zhong
AU - Wu, Jueheng
AU - Liu, Lei
AU - Song, Junwei
AU - Guan, Hongyu
AU - Cai, Junchao
AU - Zhu, Xun
AU - Li, Jun
AU - Li, Mengfeng
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Paradoxically, during early tumor development in many cancer types, TGF-β acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-β expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-β signaling toward its prometastatic role in cancer cells. Our current study using non-small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-β-induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-β-mediated metastasis. Our findings provide a mechanism that directs TGF-β signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-β for NSCLC.
AB - Paradoxically, during early tumor development in many cancer types, TGF-β acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-β expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-β signaling toward its prometastatic role in cancer cells. Our current study using non-small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-β-induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-β-mediated metastasis. Our findings provide a mechanism that directs TGF-β signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-β for NSCLC.
UR - http://www.scopus.com/inward/record.url?scp=85018960484&partnerID=8YFLogxK
U2 - 10.1172/JCI90439
DO - 10.1172/JCI90439
M3 - Article
C2 - 28375158
AN - SCOPUS:85018960484
SN - 0021-9738
VL - 127
SP - 1725
EP - 1740
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -