CCT6A Suppresses SMAD2 and Promotes Prometastatic TGF-β Signaling

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2017 Apr 5

PMID 28375158

Citations 61

Authors

Zhe Ying

Han Tian

Yun Li

Rong Lian

Wei Li

Shanshan Wu

Hui-Zhong Zhang

Jueheng Wu

Lei Liu

Junwei Song

Hongyu Guan

Junchao Cai

Xun Zhu

Jun Li

Mengfeng Li

Affiliations

Soon will be listed here.

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.

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