CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression.

BACKGROUND: UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear. METHODS: Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses. RESULTS: Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression. CONCLUSIONS: In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.

Identification of XAF1 as an endogenous AKT inhibitor.

AKT kinase is a key regulator in cell metabolism and survival, and its activation is strictly modulated. Herein, we identify XAF1 (XIAP-associated factor) as a direct interacting protein of AKT1, which strongly binds the N-terminal region of AKT1 to block its K63-linked poly-ubiquitination and subsequent activation. Consistently, Xaf1 knockout causes AKT activation in mouse muscle and fat tissues and reduces body weight gain and insulin resistance induced by high-fat diet. Pathologically, XAF1 expression is low and anti-correlated with the phosphorylated p-T308-AKT signal in prostate cancer samples, and Xaf1 knockout stimulates the p-T308-AKT signal to accelerate spontaneous prostate tumorigenesis in mice with Pten heterozygous loss. And ectopic expression of wild-type XAF1, but not the cancer-derived P277L mutant, inhibits orthotopic tumorigenesis. We further identify Forkhead box O 1 (FOXO1) as a transcriptional regulator of XAF1, thus forming a negative feedback loop between AKT1 and XAF1. These results reveal an important intrinsic regulatory mechanism of AKT signaling.

SCFFBXW7/GSK3ß-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells.

Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3ß-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7. SIGNIFICANCE: These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.