The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway
Date
2014-10-11
Authors
Salah, Zaidoun
Itzhaki, Ella
Aqeilan, Rami I.
Journal Title
Journal ISSN
Volume Title
Publisher
Impact Journals
Abstract
The Hippo kinase pathway is emerging as a conserved signaling pathway that is
essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin
E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which
leads to increased cell proliferation and decreased apoptosis. Here, we investigated
the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances
epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function.
By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished
its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in
breast cells is associated with increased incidence of mammary tumor formation and
progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis.
Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions.
Lastly, we found that ITCH expression is significantly upregulated in invasive and
metastatic breast cancer cases and is associated with worse survival. Together, our
results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at
least in part, through inactivation of the Hippo tumor suppressor pathway.