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The Shp2-induced epithelial disorganization defect is reversed by HDAC6 inhibition independent of Cdc42

Sui-Chih Tien1, Hsiao-Hui Lee2, Ya-Chi Yang1

  • 1Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Section 2, Linong Street,Taipei 11221, Taiwan.

Nature Communications
|January 20, 2016
PubMed

Insights

Oncogenic Shp2 causes abnormal epithelial cell structure by decreasing Cdc42 activity. HDAC6 suppression reverses this, restoring normal lumen formation independently of Cdc42 activity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Shp2 tyrosine phosphatase regulates cell development and disease.
  • The role of Shp2 in epithelial lumenogenesis remains unclear.
  • Deregulation of Shp2 is implicated in various pathologies.

Purpose of the Study:

  • To investigate the role of Shp2 in epithelial lumenogenesis.
  • To elucidate the mechanism by which Shp2 influences epithelial cell organization.
  • To explore therapeutic strategies targeting Shp2-mediated epithelial abnormalities.

Main Methods:

  • Investigated Shp2's effect on Tuba dephosphorylation and Cdc42 activation in epithelial cells.
  • Utilized HDAC6 suppression to reverse Shp2-induced defects in cyst lumen formation.
  • Analyzed the impact of HDAC6 inhibition on myosin II and ERK1/2 activity.
  • Examined Shp2 and HDAC6 roles in HER2-positive breast cancer cells.

Main Results:

  • Oncogenic Shp2 dephosphorylates Tuba, reducing Cdc42 activation and causing abnormal multi-lumen formation.
  • HDAC6 suppression restored normal lumenogenesis and spindle orientation in epithelial cysts.
  • HDAC6 inhibition reduced myosin II and ERK1/2 activity, independent of Cdc42 restoration.
  • HDAC6 inhibition or ERK/myosin II co-suppression promoted normal epithelial phenotype in breast cancer cells.

Conclusions:

  • Shp2 deregulation contributes to epithelial disorganization via Tuba/Cdc42 pathway.
  • HDAC6 suppression can rescue epithelial lumenogenesis defects independently of Cdc42.
  • HDAC6 inhibition offers a potential therapeutic strategy for Shp2-related epithelial disorders, including breast cancer.

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