d NTP metabolism links mechanical cues and YAP / TAZ to cell growth and oncogene‐induced senescence

  • Santinon G
  • Brian I
  • Pocaterra A
  • et al.
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Abstract

© 2018 The Authors YAP/TAZ, downstream transducers of the Hippo pathway, are powerful regulators of cancer growth. How these factors control proliferation remains poorly defined. Here, we found that YAP/TAZ directly regulate expression of key enzymes involved in deoxynucleotide biosynthesis and maintain dNTP precursor pools in human cancer cells. Regulation of deoxynucleotide metabolism is required for YAP-induced cell growth and underlies the resistance of YAP-addicted cells to chemotherapeutics targeting dNTP synthesis. During RAS-induced senescence, YAP/TAZ bypass RAS-mediated inhibition of nucleotide metabolism and control senescence. Endogenous YAP/TAZ targets and signatures are inhibited by RAS/MEK1 during senescence, and depletion of YAP/TAZ is sufficient to cause senescence-associated phenotypes, suggesting a role for YAP/TAZ in suppression of senescence. Finally, mechanical cues, such as ECM stiffness and cell geometry, regulate senescence in a YAP-dependent manner. This study indicates that YAP/TAZ couples cell proliferation with a metabolism suited for DNA replication and facilitates escape from oncogene-induced senescence. We speculate that this activity might be relevant during the initial phases of tumour progression or during experimental stem cell reprogramming induced by YAP.

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Santinon, G., Brian, I., Pocaterra, A., Romani, P., Franzolin, E., Rampazzo, C., … Dupont, S. (2018). d NTP metabolism links mechanical cues and YAP / TAZ to cell growth and oncogene‐induced senescence. The EMBO Journal, 37(11). https://doi.org/10.15252/embj.201797780

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