dNTP metabolism links mechanical cues and YAP/TAZ to cell growth and oncogene-induced senescence.
Giulia SantinonIrene BrianArianna PocaterraPatrizia RomaniElisa FranzolinChiara RampazzoSilvio BicciatoSirio DupontPublished in: The EMBO journal (2018)
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.
Keyphrases
- endothelial cells
- high glucose
- dna damage
- stem cells
- stress induced
- cell proliferation
- diabetic rats
- gene expression
- drug induced
- poor prognosis
- oxidative stress
- squamous cell carcinoma
- dna methylation
- mesenchymal stem cells
- genome wide
- induced apoptosis
- cell death
- bone marrow
- cell cycle
- cancer therapy
- single cell
- long non coding rna
- binding protein
- cell wall
- cell cycle arrest