Mechanism of tumor progression in hypoxia

Mechanism of tumor progression in hypoxia

The Hippo signalling pathway has been implicated in controlling the size of developing organs by coordinated regulation of cell growth, proliferation and apoptosis. Dysregulation of the Hippo pathway contributes to loss of cell contact inhibition, cell over-growth and epithelial–mesenchymal transition (EMT). All these factors can promote tumorigenesis and metastasis.

The large tumor suppressors (Lats1/2), the homologues of drosophila Warts, are serine/ threonine kinases and the core components of the Hippo pathway. When Hippo signalling is activated, Lats1/2 are phosphorylated and activated by Mst1/2, which allows Lats1/2 to phosphorylate the oncoproteins Yap and Taz, initiating their cytoplasm retention and deactivation, resulting in inhibition of cell growth and tumorigenesis. Reduced expression of Lats has been observed in a variety of human cancers such as colorectal cancers, prostate cancers and breast cancers, which reveals that Lats downregulation may contribute to tumorigenesis.

Upstream signals that regulate the Hippo pathway were widely studied, including physical stimuli from cell–cell contact, hypoxia and diffused chemical signal from growth factors. Transforming growth factor beta (TGF-β) was one of these growth factors that previously reported involved in regulation of the Hippo signalling, but the molecular mechanism remained elusive.

Authors previously reported that hypoxia could induce Lats2 degradation through activating E3 ubiquitin ligase Siah2, this is step one for hypoxic tumor cells to shut down the Hippo signalling. In this work, they present step two by showing that under pathophysiological conditions, such as hypoxia microenvironment, not only the activity of Siah2 is elevated, but also the secretion of TGF-β, a growth factor that has complicated function in tumour development.

They show that LIM domain protein Zyxin, as a scaffold protein, in response to hypoxia and TGF-β stimuli, forms a ternary complex with Siah2 and Lats2, thus stabilizes their interaction, and facilitates deactivation of the Hippo signalling, thereby promoting tumor progression.

Authors suggest that hypoxia-induced autocrine of TGF-β may serve as a magnifying mechanism that works together with Siah2 to negatively regulate Hippo signalling. These findings provide insights into the mechanism of TGF-β-induced deactivation of the Hippo pathway and a potential role of this regulation in tumor progression.