Hypoxia Contributes To The Tumor Development Through Deactivating The Hippo Pathway

The evolutionary conserved Hippo signaling pathway plays important role in regulation of organ development,physiology and tumorigenesis.It consists a kinases cassata that include MST1/2,LATS1/2 and downstream effectors YAP/TAZ.MST1/2 and LATS1/2 all belong to Serine/Threonine kinases and function as tumor suppressors.MST1/2 phosphorylate and activate LATS1/2 to promote the phosphorylation on YAP,causing YAP cytoplasm retention and deactivation.Large scale sequencing analysis showed that very rare cases of mutations happened within the core component of the Hippo signaling pathway.YAP is found activated in various types of cancers,indicating that the Hippo signaling pathway is deactivated in tumors.Understanding of how excellular signals regulate this pathway and how the pathway is deactivated remain major challenges.Here I show that the molecular mechanism of how hypoxic microenvironment regulates the Hippo signaling: The E3 ubiquitin ligase SIAH2 in response to hypoxia stimuli,promotes the ubiquitination and degradation of LATS2 as well as the activation of the oncoprotein YAP.In xenograft mouse model,loss of SIAH2 attenuates tumor growth in a LATS2-dependent manner.I also identify LIM domain protein Zyxin,as a scaffold protein,in response to hypoxia and TGF-β stimuli,forms a ternary complex with LATS2 and SIAH2 and stabilizes their interaction.This interaction facilitates Lats2 ubiquitination and degradation,YAP dephosphorylation and subsequently activation.I show that Zyxin is required for TGF-β and hypoxia-induced Lats2 downregulation and deactivation of Hippo signaling in MDA-MB-231 cells.Depletion of Zyxin impairs the capability of cell migration,proliferation and tumourigenesis in a xenograft model.Zyxin is upregulated in human breast cancer and positively correlates with histological stages and metastasis.Further analysis shows that YAP complexes with HIF1α,the master regulator of hypoxia response,which is essential for HIF1α stability and function in tumors.LATS2 is downregulated in breast cancer and inversely correlated with SIAH2,indicating that SIAH2-LATS2 axis may involve in the regulation of tumor development.This work demonstrates that oxygen availability as a microenvironment signal that links the crosstalk among hypoxia response,TGF-β signaling and the Hippo signaling pathway,which play important roles in the regulation of cancer development.