Cyclin F-Dependent Degradation of RBPJ Inhibits IDH1R132H-Mediated Tumorigenesis

Abstract

Cyclin F is a substrate recognition subunit of Skp1-Cul1-Fbox protein (SCF) E3 ubiquitin ligase complex. Although there have been reports describing the role of cyclin F in the genotoxic stress response, its function under conditions of altered metabolic homeostasis remain unexplored. Here we report that cyclin F is induced upon metabolic stress in a FOXO1-dependent manner. Under metabolic stress conditions, cyclin F mediated polyubiquitylation of RBPJ at Lys315, leading to its proteasomal degradation. RBPJ regulated the expression of IDH1, which is often mutated to an oncogenic form IDH1 R132H in cancers. Thus, metabolic stress-induced cyclin F attenuated the oncogenic functions of IDH1 R132H in an RBPJ-dependent manner. Studies in mouse tumor models indicated that abrogation of cyclin F expression facilitates IDH1 R132H -mediated tumorigenesis and metastasis. In addition, increased IDH1 R132H levels correlated with reduced cyclin F levels in increasing grades of glioma. These findings highlight a novel aspect of cyclin F functions in inhibiting tumorigenesis and provide mechanistic insights into regulation of IDH1 R132H .Significance: These findings reveal mechanistic insights into the key role of the cyclin F-RBPJ axis in response to metabolic stress in cancer cells. Cancer Res; 78 (22); 6386-98. Ó2018 AACR.

Cyclin F Downregulation Affects Epithelial-Mesenchymal Transition Increasing Proliferation and Migration of the A-375 Melanoma Cell Line

“…Silencing of cyclin F gene expression resulted in increased tumor size and formation of numerous metastatic nodules in the lungs and liver in an in vivo mouse model. More interestingly, this depletion evidently affected epithelial and mesenchymal markers, 15 which was consistent with our observations. The primary objective of this study was to determine the impact of cyclin F-RRM2 axis downregulation on the A-375 primary melanoma cell line in terms of hallmarks of cancer progression.…”

“…Low cyclin F has been previously reported to promote aggressiveness of hepatocellular carcinoma and glioma cells. 12 , 15 We decided to ascertain whether downregulation of cyclin F would affect the ability of A-375 cells to migrate and invade through the basement membrane. A transwell migration assay and a Matrigel invasion assay demonstrated that depletion of cyclin F expression increases the cell’s migratory ( Figure 4A and C ) and invasive ( Figure 4B and C ) capacities.…”

F-Box Proteins and Cancer

“…It has also been shown to limit centrosome duplication, with centrosome amplification being a hallmark of cancer. Furthermore, under conditions of metabolic stress, SCF Cyclin F was found to be induced and to mediate polyubiquitylation of RBP-Jκ, a mediator of Notch signaling, resulting in attenuation of the RBP-Jκ-dependent oncogenic function of the R132H mutant of isocitrate dehydrogenase 1 (IDH1) [16]. Consistent with its expected role in tumor suppression, the expression of cyclin F has been found to be down-regulated in hepatocellular carcinoma, with the extent of this down-regulation correlating with a range of prognostic markers and having been proposed as a prognostic indicator in this disease [17].…”

Molecular crosstalk between cancer and neurodegenerative diseases

“…The crucial roles of F-box proteins, including cyclin F, in tumorigenesis are gradually becoming acknowledged owing to their pivotal roles in such cases of cell cycle regulation and genome stability [189,192]. Recently, it was discovered that cyclin F is upregulated under metabolic stress conditions and inhibits tumorigenesis mediated by an oncogenic mutant form of isocitrate dehydrogenase 1 (IDH1), IDH1-R132H, in glioma [193]. Indeed, it was also reported that cyclin F is downregulated in hepatocellular carcinomas, and low cyclin F expression is correlated with poor survival and recurrence-free survival of hepatocellular carcinoma patients [194], supporting that, unlike other cyclins, cyclin F acts as a tumor suppressor and could be further investigated as a promising prognostic marker for hepatocellular carcinoma.…”