Targeting the oncogenic E3 ligase Skp2 in prostate and breast cancer cells with a novel energy restriction-mimetic agent.
Substantial evidence supports the oncogenic role of the E3 ubiquitin ligase S-phase kinase-associated protein 2 (Skp2) in many types of cancers through its ability to target a broad range of signaling effectors for ubiquitination. Thus, this oncogenic E3 ligase represents an important target for cancer drug discovery. In this study, we report a novel mechanism by which CG-12, a novel energy restriction-mimetic agent (ERMA), down-regulates the expression of Skp2 in prostate cancer cells. Pursuant to our previous finding that upregulation of β-transducin repeat-containing protein (β-TrCP) expression represents a cellular response in cancer cells to ERMAs, including CG-12 and 2-deoxyglucose, we demonstrated that this β-TrCP accumulation resulted from decreased Skp2 expression. Evidence indicates that Skp2 targets β-TrCP for degradation via the cyclin-dependent kinase 2-facilitated recognition of the proline-directed phosphorylation motif (412)SP. This Skp2 downregulation was attributable to Sirt1-dependent suppression of COP9 signalosome (Csn)5 expression in response to CG-12, leading to increased cullin 1 neddylation in the Skp1-cullin1-F-box protein complex and consequent Skp2 destabilization. Moreover, we determined that Skp2 and β-TrCP are mutually regulated, providing a feedback mechanism that amplifies the suppressive effect of ERMAs on Skp2. Specifically, cellular accumulation of β-TrCP reduced the expression of Sp1, a β-TrCP substrate, which, in turn, reduced Skp2 gene expression. This Skp2-β-TrCP-Sp1 feedback loop represents a novel crosstalk mechanism between these two important F-box proteins in cancer cells with aberrant Skp2 expression under energy restriction, which provides a proof-of-concept that the oncogenic Csn5/Skp2 signaling axis represents a "druggable" target for this novel ERMA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Shuo
S
Wei
Po-Chen
PC
Chu
Hsiao-Ching
HC
Chuang
Wen-Chun
WC
Hung
Samuel K
SK
Kulp
Ching-Shih
CS
Chen
D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism / Q000502:physiology; D044844:beta-Transducin Repeat-Containing Proteins / Q000737:chemistry / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D044786:S-Phase Kinase-Associated Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; C447939:SIRT1 protein, human; D056564:Sirtuin 1