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Fbxo32 mediated gene expression program underlies EMT and metastasis

ABSTRACT: The epithelial-mesenchymal transition (EMT) is a process by which cells lose their cell contacts and gain migratory and invasive properties. EMT is essential for numerous developmental processes including neural tube formation, in wound healing, organ fibrosis and cancer metastasis. Despite progress, the repertoire of factors involved in global transcriptional reprogramming underlying EMT remains unknown. Here we show that FBXO32, a member of the F-box protein family, is essential for phenotypic changes hallmark of EMT. Such dependency results from FBXO32-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we found that CTBP1, an established regulator of EMT, requires FBXO32 ubiquitination at Lysine 63 for its nuclear retention and gene regulatory function. FBXO32 is also highly amplified in a large panel of metastatic cancers and its knockdown severely impaired metastatic properties of cancer cells in vitro and in vivo. In addition, FBXO32 is also induced during neurogenesis and is essential for neuronal migration in vivo. Together, these findings uncover FBXO32-dependent gene regulatory circuitry that underlies EMT during development and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77408 | GEO | 2019/01/02

REPOSITORIES: GEO

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Project description:GISTs are the most common mesenchymal tumors and they display neuromuscular features. Gain-of-function mutations in KIT or PDGFRA are the initiating event in most of the cases and KIT oncogenic signaling is essential throughout all the disease. Interestingly, KIT oncogenic signaling is driven by PI3K/mTOR and RAS/MAPK pathways regardless of KIT primary or secondary mutations. Hence, dissection of KIT-downstream pathways may result in the identification of novel KIT critical effectors and a new opportunity to overcome disease heterogeneity of resistance mechanisms in GIST. Using human clinically representative GIST cell models, we undertook pharmacological and functional screenings such as Cell titer glo, kinase activation, apoptosis induction and proliferation to identify key signaling nodes within PI3K/mTOR and RAS/MAPK pathways. In vitro and in vivo validations were undertaken to model novel therapeutic strategies. Transcriptomic analysis (RNAseq) found essential genes co-regulated by both pathways. Functional studies, such as immunofluorescence, kinase activation, flow cytometry and proliferation were performed on a viral gene overexpression and knock-down models to elucidate their regulation and potential role in GIST biology. PI3K/mTOR and MEK1/2 are the most essential KIT-downstream mediators. Single node inhibition did not yield sustained antiproliferative and apoptotic effect, but simultaneous intermittent ablation was synergistic in vitro and in vivo, supporting the critical role of these two pathways.Transcriptomic analyses underscored FBXO32 (a SCF E3 ubiquitin-ligase and the main effector of muscular atrophy) as the most differentially expressed gene co-regulated by PI3K/mTOR and RAS/MAPK pathways. Functional studies demonstrated that FBXO32 is transcriptionally activated by FOXO3a which, in turn, is regulated by PI3K/mTOR and RAS/MAPK pathways. Notoriously, FBXO32 proved to have a pro-survival role in GIST cells. Microarray studies hinted a participation of FBXO32 in cell cycle arrest, which has been previously described as an adaptive pro-survival mechanism in GIST cells. This mechanism was further confirmed by functional studies. Remarkably, FBXO32 was expressed upon KIT inhibition in a panel of GIST cell lines, regardless the mutational status of KIT, and in a gene set database from GIST patients treated with first-line treatment, imatinib. PI3K/mTOR and MEK1/2 are the critical mediators of KIT oncogenic signaling in GIST, and their intermittent co-inhibition is an effective and well-tolerated therapeutic strategy to treat GIST tumors, independently of their KIT mutational status. FBXO32 emerges as a common mediator of KIT-downstream PI3K/mTOR and RAS/MAPK pathways with a critical pro-survival role in GIST participating in cell cycle arrest as pro-survival mechanism.

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Fbxo32 mediated gene expression program underlies EMT and metastasis

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