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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.

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Figure 1: Myc is a transcription factor for RhoA.
Figure 2: Myc regulates cell invasion through RhoA.
Figure 3: Skp2 cooperates with Myc to regulate RhoA transcription independently of Myc ubiquitylation and SCF–Skp2 E3 ligase activity.
Figure 4: Skp2 regulates cell invasion independently of SCF–Skp2 E3 ligase activity.
Figure 5: Skp2 cooperates with Myc to regulate RhoA transcription by recruiting p300.
Figure 6: Skp2 cooperates with Myc to regulate RhoA transcription by recruiting Miz1.
Figure 7: The Myc–Skp2–Miz1 complex regulates cancer metastasis in mouse model.
Figure 8: The Myc–Skp2–Miz1 complex is overexpressed and correlated with RhoA expression in metastatic prostate cancer samples.

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Acknowledgements

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 M. D. Anderson Cancer Center, the National Cancer Institute's Prostate Cancer Specialized Program of Research Excellence (SPORE) at the M.D. Anderson Cancer Center, a Department of Defense Prostate Cancer New Investigator Award (to H.K.L.) and a grant from the Department of Health, Taiwan (to C.F.L.).

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C.H.C. and H.K.L. designed the experiments and wrote the manuscript. C.H.C., H.K.L., S.W.L., J.W., W.L.Y., C.Y.W. and J.W. performed the experiments. H.Y.K., C.F.L. and H.Y.H. performed the immunochemistry and analysed the data. M.C.H. and P.P.P. provided the cell lines and reagents. K.I.N. provided the Skp2−/− mice.

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Correspondence to Hui-Kuan Lin.

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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

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