Statin suppresses Hippo pathway-inactivated malignant mesothelioma cells and blocks the YAP/CD44 growth stimulatory axis

Cancer Lett. 2017 Jan 28;385:215-224. doi: 10.1016/j.canlet.2016.10.020. Epub 2016 Oct 20.

Abstract

Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation. Importantly, we discovered that YAP/TEAD activated CD44 transcription by binding to the CD44 promoter at TEAD-binding sites. On the other hand, CD44 regulated Merlin phosphorylation according to cell density and sequentially promoted YAP transcriptional co-activator, suggesting that CD44 plays two pivotal functional roles as an upstream suppressor of the Hippo pathway and one of downstream targets regulated by YAP/TEAD. Moreover, the YAP/CD44 axis conferred cancer stem cell (CSC)-like properties in MM cells leading to chemoresistance, which was blocked by statin. Together, our findings suggest that YAP mediates CD44 up-regulation at the transcriptional level, conferring CSC-like properties in MM cells, and statin represents a potential therapeutic option against MM by inactivating YAP.

Keywords: CD44; Cancer stem cell; Hippo pathway; Malignant mesothelioma; Statin; YAP.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fluvastatin
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Indoles / pharmacology*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mesothelioma / drug therapy*
  • Mesothelioma / genetics
  • Mesothelioma / metabolism
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Mevalonic Acid / metabolism
  • Mutation
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Signal Transduction / drug effects
  • Simvastatin / pharmacology*
  • Time Factors
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • BAP1 protein, human
  • CD44 protein, human
  • Fatty Acids, Monounsaturated
  • Hyaluronan Receptors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Neurofibromin 2
  • Phosphoproteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YAP1 protein, human
  • Fluvastatin
  • Simvastatin
  • LATS2 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Ubiquitin Thiolesterase
  • Mevalonic Acid