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Mol Oncol. 2014 Mar;8(2):285-96. doi: 10.1016/j.molonc.2013.11.006. Epub 2013 Dec 3.

SUMOylation of RhoGDIα is required for its repression of cyclin D1 expression and anchorage-independent growth of cancer cells.

Author information

  • 1Nelson 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.
  • 2Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
  • 3Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi'an, Shannxi 710032, China.
  • 4Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA. Electronic address: Chuanshu.huang@nyumc.org.

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.

KEYWORDS:

Anchorage-independent growth; Cyclin D1; Growth arrest; RhoGDIα; SUMOylation

PMID:
24342356
PMCID:
PMC3943698
DOI:
10.1016/j.molonc.2013.11.006
[PubMed - indexed for MEDLINE]
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