Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis
Author: ["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"]
Publication: Nature Cell Biology
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Abstract
A complex containing the oncogene Myc, Skp2 E3 ligase and the coactivators Miz1 and p300 promotes transcription of RhoA. Overexpression of this complex increases RhoA levels and is detected in metastatic human cancers. 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.
Cite this article
Chan, CH., Lee, SW., Li, CF. et al. Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 12, 457–467 (2010). https://doi.org/10.1038/ncb2047
