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

Sui-Chih Tien, Hsiao-Hui Lee, Ya-Chi Yang, Miao-Hsia Lin, Yu-Ju Chen and Zee-Fen Chang ()
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Sui-Chih Tien: Institute of Biochemistry and Molecular Biology, National Yang-Ming University
Hsiao-Hui Lee: National Yang-Ming University
Ya-Chi Yang: Institute of Biochemistry and Molecular Biology, National Yang-Ming University
Miao-Hsia Lin: Institute of Chemistry, Academia Sinica
Yu-Ju Chen: Institute of Chemistry, Academia Sinica
Zee-Fen Chang: Institute of Biochemistry and Molecular Biology, National Yang-Ming University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Regulation of Shp2, a tyrosine phosphatase, critically influences the development of various diseases. Its role in epithelial lumenogenesis is not clear. Here we show that oncogenic Shp2 dephosphorylates Tuba to decrease Cdc42 activation, leading to the abnormal multi-lumen formation of epithelial cells. HDAC6 suppression reverses oncogenic Shp2-induced multiple apical domains and spindle mis-orientation during division in cysts to acquire normal lumenogenesis. Intriguingly, Cdc42 activity is not restored in this rescued process. We present evidence that simultaneous reduction in myosin II and ERK1/2 activity by HDAC6 inhibition is responsible for the reversion. In HER2-positive breast cancer cells, Shp2 also mediates Cdc42 repression, and HDAC6 inhibition or co-suppression of ERK/myosin II promotes normal epithelial lumen phenotype without increasing Cdc42 activity. Our data suggest a mechanism of epithelial disorganization by Shp2 deregulation, and reveal the cellular context where HDAC6 suppression is capable of establishing normal epithelial lumenogenesis independent of Cdc42.

Date: 2016
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DOI: 10.1038/ncomms10420

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