Dataset Information

Deubiquitinase USP9X deubiquitinates ?-catenin and promotes high grade glioma cell growth.

ABSTRACT: ?-catenin is a crucial signal transduction molecule in the Wnt/?-catenin signal pathway, and increased ?-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for ?-catenin overexpression have remained elusive.Here we show that the deubiquitinase USP9X stabilizes ?-catenin and thereby promotes high grade glioma cell growth. USP9X binds ?-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark ?-catenin for proteasomal degradation. Increased USP9X expression correlates with increased ?-catenin protein in high grade glioma tissues. Moreover, patients with high grade glioma overexpressing USP9X have a poor prognosis. Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells. Interestingly, c-Myc and cyclinD1, which are important downstream target genes in the Wnt/?-catenin signal pathway, also show decreased expression in cells with siRNA-mediated down-regulation of USP9X. Down-regulation of USP9X also consistently inhibits the tumorigenicity of primary glioma cells in vivo.In summary, these results indicate that USP9X stabilizes ?-catenin and activates Wnt/?-catenin signal pathway to promote glioma cell proliferation and survival. USP9X could also potentially be a novel therapeutic target for high grade gliomas.

SUBMITTER: Yang B

PROVIDER: S-EPMC5346732 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth.

Yang Bo B Zhang Shiming S Wang Zhihao Z Yang Chunxu C Ouyang Wen W Zhou Fuxiang F Zhou Yunfeng Y Xie Conghua C

Oncotarget 20161101 48

β-catenin is a crucial signal transduction molecule in the Wnt/β-catenin signal pathway, and increased β-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for β-catenin overexpression have remained elusive.Here we show that the deubiquitinase USP9X stabilizes β-catenin and thereby promotes high grade glioma cell growth. USP9X binds β-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark β-catenin for proteasomal degr ...[more]

PMID: 27783990

Similar Datasets

Project description:Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.

Dataset Information

Deubiquitinase USP9X deubiquitinates ?-catenin and promotes high grade glioma cell growth.

Publications

Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets