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Nat Cell Biol. 2010 May;12(5):457-67. doi: 10.1038/ncb2047. Epub 2010 Apr 11.

Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
2
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
3
Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
4
Department of Chinese Medicine; Chang Gung Memorial Hospital-Kaohsiung Medical Center; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University; Kaohsiung, Taiwan.
5
Graduate Institute of Clinical Medical Sciences, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
6
State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
7
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
8
Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center; Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
9
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan.
10
Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
#
Contributed equally

Abstract

The RhoA GTPase is crucial in numerous biological functions and is linked to cancer metastasis. However, the understanding of the molecular mechanism responsible for RhoA transcription is still very limited. Here we show that RhoA transcription is orchestrated by the Myc-Skp2-Miz1-p300 transcriptional complex. Skp2 cooperates with Myc to induce RhoA transcription by recruiting Miz1 and p300 to the RhoA promoter independently of Skp1-Cullin-F-box protein containing complex (SCF)-Skp2 E3 ligase activity. Deficiency of this complex results in impairment in RhoA expression, cell migration, invasion, and breast cancer metastasis, recapitulating the phenotypes observed in RhoA knockdown, and RhoA restoration rescues the defect in cell invasion. Overexpression of the Myc-Skp2-Miz1 complex is found in metastatic human cancers and is correlated with RhoA expression. Our study provides insight into how oncogenic Skp2 and Myc coordinate to induce RhoA transcription and establishes a novel SCF-Skp2 E3-ligase-independent function for oncogenic Skp2 in transcription and cancer metastasis.

PMID:
20383141
PMCID:
PMC3855841
DOI:
10.1038/ncb2047
[Indexed for MEDLINE]
Free PMC Article
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