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Cilia loss sensitizes Cells to transformation by activating the mevalonate pathway

2018-03-01 12:43  
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Cilia loss sensitizes cells to transformation by activating the mevalonate pathway

Yue-Zhen Deng, Zhen Cai, Shuo Shi, Hao Jiang, Yu-Rong Shang, Ning Ma, Jing-Jing Wang, Dong-Xian Guan, Tian-Wei Chen, Ye-Fei Rong, Zhen-Yu Qian, Er-Bin Zhang, Dan Feng, Quan-Li Zhou, Yi-Nan Du, Dong-Ping Liu, Xing-Xu Huang, Lu-Ming Liu, Eugene Chin, Dang-Sheng Li, Xiao-Fan Wang, Xue-Li Zhang Correspondence email, View ORCID ProfileDong Xie Correspondence email

DOI: 10.1084/jem.20170399 | Published December 13, 2017

Abstract

Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through β catenin–T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by β-catenin–TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D, which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.

Submitted: 2 March 2017
Revision received 11 September 2017
Accepted: 23 October 2017

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