SHOX2 cooperates with STAT3 to promote breast cancer metastasis through the transcriptional activation of WASF3.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE
    • Publication Information:
      Publication: 2009- : London : BioMed Central
      Original Publication: [Roma] : APSIT,
    • Subject Terms:
      Neoplasm Metastasis* ; Transcriptional Activation*; Breast Neoplasms/*pathology ; Homeodomain Proteins/*metabolism ; STAT3 Transcription Factor/*metabolism ; Wiskott-Aldrich Syndrome Protein Family/*genetics; Animals ; Cell Line, Tumor ; Cell Proliferation ; Female ; Humans ; Mice ; Mice, Inbred NOD ; Promoter Regions, Genetic ; Protein Binding ; Signal Transduction
    • Abstract:
      Background: Metastasis is most often the root cause of cancer-related death. Human short stature homeobox 2 (SHOX2), a homeodomain transcription factor, is a novel inducer of epithelial-to-mesenchymal transition in breast cancer cells, though its exact role and underlying mechanisms in metastasis are not well understood.
      Methods: TCGA analysis was performed to identify the clinical relevance of SHOX2 in breast cancer. Gene depletion was achieved by short hairpin RNA and small interfering RNA. Molecular regulations and alterations were assessed by Western blotting, immunoprecipitation, immunohistochemistry, qRT-PCR, chromatin immunoprecipitation coupled with qPCR (ChIP-qPCR), and ChIP/re-ChIP. The impact of SHOX2 signaling on tumor growth and metastasis was evaluated in orthotopic breast tumor mice.
      Results: The expression level of SHOX2 is strongly associated with poor distant metastasis-free survival in breast cancer patients and inactivation of SHOX2 suppresses breast tumor growth and metastasis in mice. In breast cancer cells, SHOX2 directly activates Wiskott-Aldridge syndrome protein family member 3 (WASF3), a metastasis-promoting gene, at the transcriptional level, leading to a significant increase in metastatic potential. Mechanistically, SHOX2 activates signal transducer and activator of transcription 3 (STAT3) and recruits it to the WASF3 promoter, where STAT3 cooperates with SHOX2 to form a functional immunocomplex to promote WASF3 transcriptional activity in breast cancer cells. WASF3 knockdown abrogates SHOX2-induced metastasis, but not SHOX2-dependent tumorigenesis.
      Conclusions: These findings provide a critical link between the SHOX2-STAT3-WASF3 signaling axis and metastasis and suggest that the targeting of this signaling node may represent a valuable alternative strategy for combating breast cancer metastasis.
      (© 2021. The Author(s).)
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    • Grant Information:
      P20 GM103499 United States GM NIGMS NIH HHS; P20GM103499-20 United States GM NIGMS NIH HHS; R03 DE028387 United States DE NIDCR NIH HHS; R01DE028351 United States DE NIDCR NIH HHS; R03DE028387 United States DE NIDCR NIH HHS
    • Contributed Indexing:
      Keywords: Breast cancer; Metastasis; SHOX2; STAT3; Transcriptional activation; WASF3
    • Accession Number:
      0 (Homeodomain Proteins)
      0 (SHOX2 protein, human)
      0 (STAT3 Transcription Factor)
      0 (STAT3 protein, human)
      0 (WASF3 protein, human)
      0 (Wiskott-Aldrich Syndrome Protein Family)
    • Publication Date:
      Date Created: 20210901 Date Completed: 20220105 Latest Revision: 20240507
    • Publication Date:
      20240507
    • Accession Number:
      PMC8406721
    • Accession Number:
      10.1186/s13046-021-02083-6
    • Accession Number:
      34465361