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

doi:10.1038/ncb2047

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

Department of Molecular and Cellular Biology

Research output: Contribution to journal › Article › peer-review

174 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 language	English
Pages (from-to)	457-467
Number of pages	11
Journal	Nature Cell Biology
Volume	12
Issue number	5
DOIs	https://doi.org/10.1038/ncb2047
Publication status	Published - May 2010

All Science Journal Classification (ASJC) codes

Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncb2047

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@article{4ce5bdb018774bd09d496dc17dc0c8a6,

title = "Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis",

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.",

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

note = "Funding Information: We thank R. Weinberg, W. Sellers, D. Bohmann, W. Tansey, J. M. Sedivy, W. Wei, M. Pagano, M. Eilers, W. S. El-Deiry, L. Yao and D. Sarbassov for reagents. We also thank D. Sarbassov, M. H. Lee and M. G. Lee for comments and suggestions. Special thanks are extended to S. Patterson for editing and critical reading of the manuscript. This work was supported by Research Trust Scholar funds from the",

year = "2010",

month = may,

doi = "10.1038/ncb2047",

language = "English",

volume = "12",

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AU - Chan, Chia Hsin

AU - Lee, Szu Wei

AU - Li, Chien Feng

AU - Wang, Jing

AU - Yang, Wei Lei

AU - Wu, Ching Yuan

AU - Wu, Juan

AU - Nakayama, Keiichi I.

AU - Kang, Hong Yo

AU - Huang, Hsuan Ying

AU - Hung, Mien Chie

AU - Pandolfi, Pier Paolo

AU - Lin, Hui Kuan

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PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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.

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

Abstract

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