title: SUMOylation of RhoGDIα is required for its repression of cyclin D1 expression and anchorage-independent growth of cancer cells.
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.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA; Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi'an, Shannxi 710032, China.
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Xueyong
authors.initials: X
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi'an, Shannxi 710032, China.
authors.forename: Beipei
authors.initials: B
authors.lastname: Kang
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi'an, Shannxi 710032, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi'an, Shannxi 710032, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA. Electronic address: Chuanshu.huang@nyumc.org.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D014158:Transcription, Genetic / Q000235:genetics; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; D016755:Proto-Oncogene Proteins c-jun; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D019938:Cyclin D1
keywords: Anchorage-independent growth; Cyclin D1; Growth arrest; RhoGDIα; SUMOylation