Restriction of Glioma Progression and Mesenchymal Characteristics by Angiomotin-like 1

Abstract

Angiomotin-like 1 (AmotL1) serves as a scaffold for protein complexes that promote cell polarity and HIPPO signaling to enable their suppression of oncogenic phenotypes in multiple epithelial-derived cancers. In this study, an analysis of multiple tumor databases revealed that AmotL1 transcript levels associate with positive survival and reduced tumor grade in astrocytomas. The suppression of AmotL1 transcript levels was most prevalent in in glioblastoma tumor regions that are associated with invasion and mesenchymal-like transcriptional profiles. Factors associated with tumor progression were consequently causally linked to AmotL1 expression in normal astrocytes and glioblastoma cells. While most tumor suppressive effects of AmotL1 are related to its regulation of YAP and TAZ, the potent effects of AmotL1 down-regulation were found to be independent of these two oncoproteins. Further, AmotL1 was shown to inhibit Wnt signaling through binding of the Fzd4 receptor via MAGI-3. Such binding was associated with an ability by AmotL1 to redistribute Fzd4 from the cell surface to intracellular complexes with AmotL1 and MAGI-3. AmotL1 was also shown to be transcriptionally suppressed under hypoxia by HIF2α. This suppression was found to promote invasion by increasing levels of c-MET. These results show that hypoxia suppresses AmotL1 to promote a likely mesenchymal transition. These effects help to explain the association of AmotL1 down-regulation in glioblastomas with increased tumor grade and poor patient survival.