TAZ and YAP are frequently activated oncoproteins in sarcomas

Oncotarget. 2016 May 24;7(21):30094-108. doi: 10.18632/oncotarget.8979.

Abstract

TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP.

Keywords: Hippo pathway; Pathology Section; TAZ; WWTR1; YAP; sarcoma.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinogenesis / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Connective Tissue Growth Factor / metabolism
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Muscle Proteins / metabolism*
  • Neoplasm Grading
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Porphyrins / pharmacology*
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • RNA, Small Interfering
  • Sarcoma / drug therapy
  • Sarcoma / metabolism*
  • Sarcoma / pathology
  • Signal Transduction / drug effects
  • Tissue Array Analysis
  • Transcription Factors / metabolism*
  • Verteporfin

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CCN2 protein, human
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Oncogene Proteins
  • Phosphoproteins
  • Porphyrins
  • RNA, Small Interfering
  • TEAD4 protein, human
  • Transcription Factors
  • WWTR1 protein, human
  • YAP1 (Yes-associated) protein, human
  • Verteporfin
  • Connective Tissue Growth Factor
  • Protein-Serine-Threonine Kinases