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

Chia Hsin Chan, Szu Wei Lee, Chien Feng Li, Jing Wang, Wei Lei Yang, Ching Yuan Wu, Juan Wu, Keiichi I. Nakayama, Hong Yo Kang, Hsuan Ying Huang, Mien Chie Hung, Pier Paolo Pandolfi, Hui Kuan Lin

Research output: Contribution to journalArticle

148 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)457-467
Number of pages11
JournalNature Cell Biology
Volume12
Issue number5
DOIs
Publication statusPublished - May 1 2010

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Chan, C. H., Lee, S. W., Li, C. F., Wang, J., Yang, W. L., Wu, C. Y., Wu, J., Nakayama, K. I., Kang, H. Y., Huang, H. Y., Hung, M. C., Pandolfi, P. P., & Lin, H. K. (2010). Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nature Cell Biology, 12(5), 457-467. https://doi.org/10.1038/ncb2047