Cyclin F-Dependent Degradation of RBPJ Inhibits IDH1^R132H-Mediated Tumorigenesis.

Abstract

Cyclin F is a substrate recognition subunit of Skp1-Cul1-F-box 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 <i>cyclin F</i> 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 <i>IDH1^R132H</i> <b>Significance:</b> These findings reveal mechanistic insights into the key role of the cyclin F-RBPJ axis in response to metabolic stress in cancer cells. <i>Cancer Res; 78(22); 6386-98. ©2018 AACR</i>.