title: CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling.
abstract: 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.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.forename: Han
authors.initials: H
authors.lastname: Tian
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Lian
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wu
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Junwei
authors.initials: J
authors.lastname: Song
authors.forename: Hongyu
authors.initials: H
authors.lastname: Guan
authors.forename: Junchao
authors.initials: J
authors.lastname: Cai
authors.forename: Xun
authors.initials: X
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D056404:Chaperonin Containing TCP-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C533302:CCT6A protein, human; C000607571:CCT6A protein, mouse; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D056404:Chaperonin Containing TCP-1