Abstract
Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.
Highlights
Glioblastoma (GBM), the most common and malignant adult primary brain cancer, is essentially incurable with median survivals of only 12–16 months from diagnosis
Mesenchymal changes in GBM, which are similar to epithelial mesenchymal transition (EMT) in other cancers, promote canonical features of malignancy including cell invasion, cancer cell stemness, and treatment resistance contributing to poor prognoses [3,4,5,6]
We confirmed the presence of TW S68 phosphorylation at the endogenous level in glioma cells and patient-derived GBM cell lines to establish its potential relevance for GBM tumor cell specific phenotypes
Summary
Glioblastoma (GBM), the most common and malignant adult primary brain cancer, is essentially incurable with median survivals of only 12–16 months from diagnosis. One potential therapeutic target is mechanisms, which promote mesenchymal transition [1,2]. In GBM we demonstrated that TW promotes mesenchymal change by regulating invasion, GBM stem cell self-renewal and tumorigenicity [9,10]. Expression of POSTN is regulated by, and directly correlates with, TW expression in human gliomas, and like TW, promotes invasion and tumorigenicity of GBM cells [11]. While these observations support the potential therapeutic relevance of TW-POSTN signaling, the mechanisms by which TW may regulate POSTN expression in GBM and other cancers are not known. Potential candidate mechanisms include active site-specific TW phosphorylation and TW dimerization motifs with functional relevance in development and cancer
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