Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway

Aleksandra Toloczko, Fusheng Guo, Hiu-Fung Yuen, Qing Wen, Stephen A Wood, Yan Shan Ong, Pei Yi Chan, Asfa Alli Shaik, Jayantha Gunaratne, Mark J Dunne, Wanjin Hong, Siew Wee Chan

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth. Cancer Res; 77(18); 4921-33. ©2017 AACR.

Original languageEnglish
Pages (from-to)4921-4933
JournalCancer Research
Volume77
Issue number18
Early online date18 Jul 2017
DOIs
Publication statusPublished - 15 Sep 2017

Keywords

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis
  • Biomarkers, Tumor
  • Breast Neoplasms
  • Cell Proliferation
  • Cells, Cultured
  • Embryo, Mammalian
  • Endopeptidases
  • Female
  • Fibroblasts
  • Follow-Up Studies
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neoplasm Staging
  • Pancreatic Neoplasms
  • Phosphoproteins
  • Phosphorylation
  • Prognosis
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Survival Rate
  • Transcription Factors
  • Ubiquitin Thiolesterase
  • Ubiquitination
  • Journal Article

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