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ROC1/RBX1 E3 Ubiquitin Ligase Silencing Suppresses Tumor Cell Growth via Sequential Induction of G₂-M Arrest, Apoptosis, and Senescence

¹ Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan and ² Melanoma Group, Molecular Pathology Program, Spanish National Cancer Research Institute, Madrid, Spain

Requests for reprints: Yi Sun, University of Michigan, 4424B Medical Science Building-I, 1301 Catherine Street, Ann Arbor, MI 48109-5637. Phone: 734-615-1989; Fax: 734-763-1581; E-mail: sunyi{at}umich.edu.

Key Words: ROC1/RBX1 • SCF ubiquitin ligases • siRNA silencing • senescence • apoptosis • G₂-M arrest

Regulator of Cullins-1 (ROC1) or Ring Box Protein-1 (RBX1) is a RING component of SCF (Skp-1, cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting a variety of substrates for degradation. However, little is known about the role of ROC1 in human cancer. Here, we report that ROC1 is ubiquitously overexpressed in primary human tumor tissues and human cancer cell lines. ROC1 silencing by siRNA significantly inhibited the growth of multiple human cancer cell lines via induction of senescence and apoptosis as well as G₂-M arrest. Senescence induction is coupled with DNA damage in p53/p21- and p16/pRB-independent manners. Apoptosis is associated with accumulation of Puma and reduction of Bcl-2, Mcl-1, and survivin; and G₂-M arrest is associated with accumulation of 14-3-3 and elimination of cyclin B1 and Cdc2. In U87 glioblastoma cells, these phenotypic changes occur sequentially upon ROC1 silencing, starting with G₂-M arrest, followed by apoptosis and senescence. Thus, ROC1 silencing triggers multiple death and growth arrest pathways to effectively suppress tumor cell growth, suggesting that ROC1 may serve as a potential anticancer target. [Cancer Res 2009;69(12):4974–82]