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Cited by 209Protein Kinase Regulation and GTPase SignalingUbiquitin and proteasome pathwaysMechanisms of cancer metastasis

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

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Chan, Chia-Hsin, Lee, Szu-Wei, Li, Chien-Feng, Wang, Jing, Yang, Wei-Lei, Wu, Ching-Yuan, Wu, Juan, Nakayama, Keiichi I. +5 more·2010·Nature Cell Biology
DOI 10.1038/ncb2047PMC PMC3855841
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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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  • In breast cancer cells, c-Myc heterodimerizes with Max and binds to the E-box motif CACGTG in the RHOA promoter in cooperation with Skp2-Miz1-p300, activating RHOA transcription.

    “In breast cancer cells, c-Myc has been found to heterodimerize with the transcription factor Max and to bind to the E-box motif CACGTG in the RHOA promoter in cooperation with the coactivator complex Skp2-Miz1-p300, hereby activating RHOA transcription [84].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [84]

    The Results sections report Myc and Max at the RhoA promoter and show that Skp2, Miz1, and p300 cooperate with Myc to activate RhoA transcription. But the claimed binding site is wrong: the Results say the canonical CACGTG-containing promoter fragment was not induced by Myc; Myc-dependent activation instead involved noncanonical E-boxes 5 and 6 (CACGCG). (LLM, conf=0.89)

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Authors
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.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Chi Mei Medical Center (TW)
  • Kyushu University (JP)
  • Chang Gung University (TW)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Lin, Hui-Kuan
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2010-04-11
Volume
12
Issue
5
Pages
457-467
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb2047
PMC
PMC3855841
OpenAlex
W2025519885
Cited by
209
References
0
Citations by year
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FWCI
6.68
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders
National Cancer Institute (R01CA136787)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
c-Myc, Skp2, Miz-1, P300, transcriptional complex, metastasis, breast cancer, cell invasion, cell migration, RhoA GTPase
MeSH terms
Animals, Cell Line, Humans, Neoplasm Metastasis, Neoplasms, Nuclear Proteins, Promoter Regions, Genetic, Transcription, Genetic, Oncogene Protein p55(v-myc), Mice, Knockout, rhoA GTP-Binding Protein, Ubiquitin-Protein Ligases, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, Multiprotein Complexes, Protein Inhibitors of Activated STAT, E1A-Associated p300 Protein, Mice

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