Contact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis.
Park, So Jung
Menzies, Fiona M
Lombarte, Alejandro Carnicer
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Pavel, M., Renna, M., Park, S. J., Menzies, F. M., Ricketts, T., Füllgrabe, J., Ashkenazi, A., et al. (2018). Contact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis.. Nature communications, 9 (1), 2961. https://doi.org/10.1038/s41467-018-05388-x
Contact inhibition enables noncancerous cells to cease proliferation and growth when they contact each other. This characteristic is lost when cells undergo malignant transformation, leading to uncontrolled proliferation and solid tumour formation. Here we report that autophagy is compromised in contact-inhibited cells in 2D or 3D-soft extracellular matrix cultures. In such cells, YAP/TAZ fail to co-transcriptionally regulate the expression of myosin-II genes, resulting in the loss of F-actin stress fibers, which impairs autophagosome formation. The decreased proliferation resulting from contact inhibition is partly autophagy-dependent, as is their increased sensitivity to hypoxia and glucose starvation. These findings define how mechanically repressed YAP/TAZ activity impacts autophagy to contribute to core phenotypes resulting from high cell confluence that are lost in various cancers.
Cell Line, Tumor, Hela Cells, Extracellular Matrix, Fibroblasts, Epithelial Cells, Animals, Humans, Mice, Actins, Myosin Type II, Glucose, Adaptor Proteins, Signal Transducing, Phosphoproteins, Transcription Factors, Cell Count, Signal Transduction, Apoptosis, Cell Proliferation, Cell Survival, Contact Inhibition, Autophagy, CapZ Actin Capping Protein, Gene Knockdown Techniques, Actin Cytoskeleton, Hypoxia, Autophagosomes
This work was supported by the Wellcome Trust (Principal Research Fellowship to DCR (095317/Z/11/Z)), a Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), MRC and Sackler Foundation (doctoral training grant RG70550 to ACL), NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital, the Treat PolyQ project (European community’s Seventh Framework Programme under grant agreement No. 264508), a Romanian grant of Ministery of Research and Innovation CNCS –UEFISCDI, project number PN-III-P1-1.1-PD-2016-1291, within PNCDI III (to MP).
Wellcome Trust (095317/Z/11/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG50822)
Wellcome Trust (100140/Z/12/Z)
EC FP7 MC ITN (264508)
External DOI: https://doi.org/10.1038/s41467-018-05388-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279830
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/