Editors' ChoiceCancer

Hypoxia and Hippo Signaling

Science Signaling  13 Jan 2015:
Vol. 8, Issue 359, pp. ec10
DOI: 10.1126/scisignal.aaa6564

Cells and tissues survive hypoxia in part by activating the ubiquitin E3 ligase SIAH2, resulting in the stabilization of the transcription factor HIF-1α, which stimulates the expression of proangiogenic genes. The transcriptional coactivator YAP is phosphorylated and inactivated by the kinases LATS1 and LATS2 of the Hippo pathway, which limits cell growth and proliferation. Ma et al. found that hypoxia inactivated Hippo signaling, which in turn enabled the interaction of YAP and HIF-1α and reinforced the hypoxia-induced stabilization of HIF-1α. LATS2 was ubiquitinated at Lys670 and Lys762 by SIAH2. LATS2 abundance was decreased in hypoxic MDA-MB-231 cells, resulting in reduced phosphorylation of YAP and increased expression of YAP target genes. Cell proliferation and survival of MDA-MB-231 cells under hypoxic conditions and xenografted tumor growth in mice was reduced by SIAH2 knockdown, effects that were ablated by concomitant knockdown of LATS2. Low LATS2 abundance correlated with high SIAH2 abundance in breast cancer tissue microarrays. YAP knockdown decreased the stabilization of HIF-1α in hypoxic MDA-MB-231 cells and the growth, microvessel density, and expression of the HIF-1α target gene VEGF in xenografted tumors in mice. These effects were attenuated by reconstitution with wild-type or phosphorylation-deficient forms of YAP, but not with a phosphorylation-mimetic form of YAP. The activity of a hypoxia-response element (HRE)–containing luciferase reporter was decreased by LATS2 overexpression and increased by expression of the phosphorylation-deficient YAP mutant. Immunoprecipitation analysis of MDA-MB-231 cells indicated that YAP interacted with HIF-1α and that this interaction was increased by hypoxia, and ChIP analysis revealed that YAP and HIF-1α were present at the HRE of the VEGF promoter in response to hypoxia. Thus, deactivation of Hippo signaling by hypoxia reinforces the transcriptional response to hypoxia.

B. Ma, Y. Chen, L. Chen, H. Cheng, C. Mu, J. Li, R. Gao, C. Zhou, L. Cao, J. Liu, Y. Zhu, Q. Chen, S. Wu, Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat. Cell Biol. 17, 95–103 (2015). [PubMed]