ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence.
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 G(2)-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 G(2)-M arrest is associated with accumulation of 14-3-3sigma and elimination of cyclin B1 and Cdc2. In U87 glioblastoma cells, these phenotypic changes occur sequentially upon ROC1 silencing, starting with G(2)-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.
Jia
Lijun
L
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Soengas
Maria S
MS
Sun
Yi
Y
D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D017931:DNA Primers; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*
D002352:Carrier Proteins; D017931:DNA Primers; C479529:RBX1 protein, human