Title: SUMOylation of RhoGDIα is required for its repression of cyclin D1 expression and anchorage-independent growth of cancer cells.
Authors: Cao, Zipeng; Li, Xueyong; Li, Jingxia; Kang, Beipei; Chen, Jingyuan; Luo, Wenjing; Huang, Chuanshu
Published In Mol Oncol, (2014 Mar)
Abstract: Selective activation of Rho GTPase cascade requires the release of Rho from RhoGDI (GDP-dissociation inhibitors) complexes. Our previous studies identified RhoGDIα SUMOylation at Lys-138 and its function in the regulation of cancer cell invasion. In the current study, we demonstrate that RhoGDIα SUMOylation has a crucial role in the suppression of cancer cell anchorage-independent growth as well as the molecular mechanisms underlying this suppression. We found that ectopic expression of RhoGDIα resulted in marked inhibition of an anchorage-independent growth with induction of G0/G1 cell cycle arrest, while point mutation of RhoGDIα SUMOylation at residue Lys-138 (K138R) abrogated this growth suppression and G0/G1 cell cycle arrest in cancer cells. Further studies showed that SUMOylation at Lys-138 was critical for RhoGDIα down-regulation of cyclin D1 protein expression and that MEK1/2-Erk was a specific downstream target of SUMOylated RhoGDIα for its inhibition of C-Jun/AP-1 cascade, cyclin d1 transcription, and cell cycle progression. These results strongly demonstrate that SUMOylated RhoGDIα suppressed C-Jun/AP-1-dependent transactivation specifically via targeting MEK1/2-Erk, subsequently leading to the down-regulation of cyclin D1 expression and anti-cancer activity. Our results provide new mechanistic insights into the understanding of essential role of SUMOylation at Lys-138 in RhoGDIα's biological function.
PubMed ID: 24342356
MeSH Terms: Amino Acid Substitution; Cell Line, Tumor; Cyclin D1/genetics; Cyclin D1/metabolism*; G1 Phase Cell Cycle Checkpoints*; Gene Expression Regulation, Neoplastic/genetics; Humans; MAP Kinase Signaling System/genetics; Neoplasms/genetics; Neoplasms/metabolism*; Neoplasms/pathology; Point Mutation*; Proto-Oncogene Proteins c-jun/genetics; Proto-Oncogene Proteins c-jun/metabolism; Sumoylation*; Transcription, Genetic/genetics; rho Guanine Nucleotide Dissociation Inhibitor alpha/genetics; rho Guanine Nucleotide Dissociation Inhibitor alpha/metabolism*