Details

Autor(en) / Beteiligte

• Mikheev, Andrei M.
• Mikheeva, Svetlana A.
• Severs, Liza J.
• Funk, Cory C.
• Huang, Lei
• McFaline‐Figueroa, José L.
• Schwensen, Jeanette
• Trapnell, Cole
• Price, Nathan D.
• Wong, Stephen
• Rostomily, Robert C.

Titel

Targeting TWIST 1 through loss of function inhibits tumorigenicity of human glioblastoma

Ist Teil von

• Molecular oncology, 2018-06, Vol.12 (7), p.1188-1202

Ort / Verlag

Hoboken: John Wiley & Sons, Inc

Erscheinungsjahr

2018

Quelle

Wiley Online Library Journals

Beschreibungen/Notizen

• TWIST1 ( TW ) is a bHLH transcription factor ( TF ) and master regulator of the epithelial‐to‐mesenchymal transition ( EMT ). In vitro , TW promotes mesenchymal change, invasion, and self‐renewal in glioblastoma ( GBM ) cells. However, the potential therapeutic relevance of TW has not been established through loss‐of‐function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87 MG and GBM 4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNA seq and the analysis of tumors investigated putative TW ‐associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM , membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI 3K/ AKT signaling. We experimentally show alteration of AKT activity and periostin ( POSTN ) expression in vivo and/or in vitro . For the first time, we show that effect of TW knockout inhibits AKT activity in U87 MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM . While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM . Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM .