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Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.

Publication ,  Journal Article
Deng, Y-Z; Cai, Z; Shi, S; Jiang, H; Shang, Y-R; Ma, N; Wang, J-J; Guan, D-X; Chen, T-W; Rong, Y-F; Qian, Z-Y; Zhang, E-B; Feng, D; Du, Y-N ...
Published in: J Exp Med
January 2, 2018
Published version (DOI) Link to item

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.

Duke Scholars

Xiao-Fan Wang
Author Xiao-Fan Wang Pharmacology & Cancer Biology
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Published In

J Exp Med

DOI

10.1084/jem.20170399

EISSN

1540-9538

Publication Date

January 2, 2018

Volume

215

Issue

1

Start / End Page

177 / 195

Location

United States

Related Subject Headings

  • TCF Transcription Factors
  • Sterol Regulatory Element Binding Protein 2
  • Pancreatic Neoplasms
  • Oncogenes
  • NIH 3T3 Cells
  • Mice
  • Mevalonic Acid
  • Metabolic Networks and Pathways
  • Male
  • Immunology
 

Citation

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Deng, Y.-Z., Cai, Z., Shi, S., Jiang, H., Shang, Y.-R., Ma, N., … Xie, D. (2018). Cilia loss sensitizes cells to transformation by activating the mevalonate pathway. J Exp Med, 215(1), 177–195. https://doi.org/10.1084/jem.20170399
Deng, Yue-Zhen, Zhen Cai, Shuo Shi, Hao Jiang, Yu-Rong Shang, Ning Ma, Jing-Jing Wang, et al. “Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.” J Exp Med 215, no. 1 (January 2, 2018): 177–95. https://doi.org/10.1084/jem.20170399.
Deng Y-Z, Cai Z, Shi S, Jiang H, Shang Y-R, Ma N, et al. Cilia loss sensitizes cells to transformation by activating the mevalonate pathway. J Exp Med. 2018 Jan 2;215(1):177–95.
Deng, Yue-Zhen, et al. “Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.” J Exp Med, vol. 215, no. 1, Jan. 2018, pp. 177–95. Pubmed, doi:10.1084/jem.20170399.
Deng Y-Z, Cai Z, Shi S, Jiang H, Shang Y-R, Ma N, Wang J-J, Guan D-X, Chen T-W, Rong Y-F, Qian Z-Y, Zhang E-B, Feng D, Zhou Q-L, Du Y-N, Liu D-P, Huang X-X, Liu L-M, Chin E, Li D-S, Wang X-F, Zhang X-L, Xie D. Cilia loss sensitizes cells to transformation by activating the mevalonate pathway. J Exp Med. 2018 Jan 2;215(1):177–195.

Published In

J Exp Med

DOI

10.1084/jem.20170399

EISSN

1540-9538

Publication Date

January 2, 2018

Volume

215

Issue

1

Start / End Page

177 / 195

Location

United States

Related Subject Headings

  • TCF Transcription Factors
  • Sterol Regulatory Element Binding Protein 2
  • Pancreatic Neoplasms
  • Oncogenes
  • NIH 3T3 Cells
  • Mice
  • Mevalonic Acid
  • Metabolic Networks and Pathways
  • Male
  • Immunology