Aberrant activation of β-catenin in the nucleus has been implicated in a variety of human cancers, but the fate of nuclear β-catenin is unknown. Here we demonstrate that the tripartite motif-containing protein 33 (TRIM33), acting as an E3 ubiquitin ligase, reduces the abundance of nuclear β-catenin protein. TRIM33-mediated β-catenin is destabilized and is GSK-3β or β-TrCP independent. TRIM33 interacts with and ubiquitylates nuclear β-catenin. Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. The function of TRIM33 in suppressing tumour cell proliferation and brain tumour development depends on TRIM33-promoted β-catenin degradation. In human glioblastoma specimens, endogenous TRIM33 levels are inversely correlated with β-catenin. In summary, our findings identify TRIM33 as a tumour suppressor that can abolish tumour cell proliferation and tumorigenesis by degrading nuclear β-catenin. This work suggests a new therapeutic strategy against human cancers caused by aberrant activation of β-catenin.

Emerging evidence has shown that GSK3β plays oncogenic roles in multiple tumour types; however, the underlying mechanisms remain largely unknown. Here, we show that nuclear GSK3β is responsible for the accumulation of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during tumorigenesis. GSK3β phosphorylates KDM1A Ser683 upon priming phosphorylation of KDM1A Ser687 by CK1α. Phosphorylation of KDM1A induces its binding with and deubiquitylation by USP22, leading to KDM1A stabilization. GSK3β- and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repressing BMP2, CDKN1A and GATA6 transcription, which results in cancer stem cell self-renewal and glioblastoma tumorigenesis. In human glioblastoma specimens, KDM1A levels are correlated with nuclear GSK3β and USP22 levels. Furthermore, a GSK3 inhibitor, tideglusib, sensitizes tumour xenografts to chemotherapy in mice via KDM1A downregulation and improves survival. Our findings demonstrate that nuclear GSK3β- and USP22-mediated KDM1A stabilization is essential for glioblastoma tumorigenesis.

The growth factor PDGF controls the development of glioblastoma (GBM), but its contribution to the function of GBM stem-like cells (GSC) has been little studied. Here, we report that the transcription factor FoxM1 promotes PDGFA-STAT3 signaling to drive GSC self-renewal and tumorigenicity. In GBM, we found a positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A expression, acting to maintain the stem-like qualities of GSC in part through this mechanism. Analysis of the human cancer genomic database The Cancer Genome Atlas revealed that GBM expresses higher levels of STAT3, a PDGF-A effector signaling molecule, as compared with normal brain. FoxM1 regulated STAT3 transcription through interactions with the β-catenin/TCF4 complex. FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties. Further mechanistic investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was sufficient to confer stem-like properties to glioma cells. Collectively, our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. Cancer Res; 75(11); 2337–48. ©2015 AACR.