FBXO32 promotes microenvironment underlying epithelial-mesenchymal transition via CtBP1 during tumour metastasis and brain development

Abstract

The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial–mesenchymal transition (EMT). EMT is involved during development, for example, in triggering neural crest migration, and in pathogenesis such as metastasis. Here we discover FBXO32, an E3 ubiquitin ligase, to be critical for hallmark gene expression and phenotypic changes underlying EMT. Interestingly, FBXO32 directly ubiquitinates CtBP1, which is required for its stability and nuclear retention. This is essential for epigenetic remodeling and transcriptional induction of CtBP1 target genes, which create a suitable microenvironment for EMT progression. FBXO32 is also amplified in metastatic cancers and its depletion in a NSG mouse xenograft model inhibits tumor growth and metastasis. In addition, FBXO32 is essential for neuronal EMT during brain development. Together, these findings establish that FBXO32 acts as an upstream regulator of EMT by governing the gene expression program underlying this process during development and disease.

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

“…The above data on FBXL5 agrees with previous research in our lab, where we discovered that FBXO32-another F-box protein-was pivotal in upstream EMT regulation not only in tumor metastasis, but in neuronal development also (102). FBXO32 directly ubiquitinated CtBP1 causing its stabilization and nuclear retention, which created a suitable microenvironment for EMT progression by facilitating epigenetic remodeling and transcription of CtBP1 target genes (102). In line with these findings, FBXO32 was amplified in metastatic cancers, and its depletion in vivo inhibited tumor growth and metastasis (102).…”

“…FBXL5/BTG3 are direct miRNA-20a targets that are silenced to enable miRNA-20a-mediated EMT and invasion (99), however the precise role of FBXL5 signaling in EMT requires further research; FBXL5 overexpression reduced Snail protein levels (100), but also supported tumorigenesis by negatively regulated PTEN while promoting PI3K/Akt and mTOR phosphorylation and expression (101). The above data on FBXL5 agrees with previous research in our lab, where we discovered that FBXO32-another F-box protein-was pivotal in upstream EMT regulation not only in tumor metastasis, but in neuronal development also (102). FBXO32 directly ubiquitinated CtBP1 causing its stabilization and nuclear retention, which created a suitable microenvironment for EMT progression by facilitating epigenetic remodeling and transcription of CtBP1 target genes (102).…”

Human iPSC-Derived Neuronal Cells From CTBP1-Mutated Patients Reveal Altered Expression of Neurodevelopmental Gene Networks

“…The neurodevelopmental phenotypes conferred by the CTBP1 mutant allele provide genetic evidence that CTBP1 is important for normal human brain development. Previous biochemical studies also suggested that CtBPs might be important for certain brain developmental functions (Sahu et al, 2017;Shen et al, 2017). CtBP1 has been reported to mediate transcriptional repression of a number of neuronal genes involved in synaptic activities of the inner ear hair cells, the retina (Ivanova et al, 2015) and the synaptic ribbon complex (Tom Dieck et al, 2005).…”

Impact of Hydrogel Elasticity and Adherence on Osteosarcoma Cells and Osteoblasts

“…However, there is no direct relationship between adherent molecules and the expression of α‐E‐catenin and β‐catenin in 3D cultured osteosarcoma cells, indicating that integrin‐AJ mediated tumorigenesis was not tightly associated with ECM adherence. And less adherent molecules conduce to the malignant cancer cells metastasize from situ to secondary focuses . This notion was further verified by in vivo findings showing that α‐E‐catenin expression is not associated with ECM adherence in cancer or even against it.…”