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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • January 2018

Published In

Volume / Issue

  • 215 / 1

Start / End Page

  • 177 - 195

PubMed ID

  • 29237705

Pubmed Central ID

  • 29237705

Electronic International Standard Serial Number (EISSN)

  • 1540-9538

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20170399

Language

  • eng