Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

Molecular Oncology
Andrei M MikheevRobert C Rostomily

Abstract

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 U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq 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 PI3K/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 U87MG 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 expressio...Continue Reading

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Citations

Jan 16, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Anna M Krichevsky, Erik J Uhlmann
Jun 17, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Xiang AoYing Liu
Feb 23, 2021·Molecular Therapy Oncolytics·Weihan WangZhifan Jia
May 21, 2021·European Journal of Pharmacology·Xuan ZhaiPing Liang

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Methods Mentioned

BETA
xenograft
xenografts
pCLIP
RNAseq
RNA seq

Software Mentioned

SAM
AMM
Ingenuity
HTseq
Ingenuity Pathways Analysis ( IPA )
LASSO
DESeq2
Gephi
Prism
KBiobox

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