Hippo signaling mediates hypoxia tumorgenesis via SIAH2


The Hippo signaling pathway, consists core kinases MST(1/2) and LATS (1/2), controls organ size via regulating cell proliferation and apoptosis. However, dysregulation of Hippo pathway is involved in tumor development. Ma et al. gives a insight into the mechanism of Hippo signaling by investigating the pathway deactivation induced by hypoxia. The letter was published on Nature Cell Biology, recently.


Firstly, researchers found hypoxia-induced SIAH2, as E3 ubiquitin ligase, downregulated LATS2 mainly by targeting two sites, Lys 670 and Lys 672. Subsequently, YAP signaling, which is a downstream factor of Hippo pathway, was observed to be enhanced accompanied by SIAH2-induced reduction of LATS2. By examination the expression levels of LATS2 and SIAH2 in breast cancer, they found the upregulation of SIAH2 and LATS2 are significantly correlated with tumorigenesis. Moreover, in xenograft tumour tissues, the decrease of HIF1α accumulation and reduction of microvessel density and Ki67-positive cells were found in response to the loss of YAP, indicating that YAP may enhance tumour growth facilitated by HIF1α. In addition, YAP dephosphorylation is required for HIF1α stabilization. These results provide a insight into SIAH2-LATS2 pathway in mediation hypoxic tumorigenesis and may give a promise therapeutic strategy against cancer related to these pathways.


Nat Cell Biol. 2014 Dec 1.10.1038/ncb3073.

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