Journal
THERANOSTICS
Volume 8, Issue 4, Pages 972-989Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.22328
Keywords
epithelial-to-mesenchymal transition; LSD1; MTA3; SIX3; tumorigenesis
Categories
Funding
- Major State Basic Research Development Program of China [2016YFA0102400]
- National Natural Science Foundation of China [81472733, 81322032, 81402334, 81502446]
- Ministry of Education of China [NCET-12-1067, FANEDD-201231, RFDP-20131202110012]
- Tianjin Medical University
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The homeodomain transcription factor SIX3 was recently reported to be a negative regulator of the Wnt pathway and has an emerging role in cancer. However, how SIX3 contributes to tumorigenesis and metastasis is poorly understood. Methods: We employed affinity purification and mass spectrometry (MS) to identify the proteins physically associated with SIX3. Genome-wide analysis of the SIX3/LSD1/NuRD(MTA3) complex using a chromatin immunoprecipitation-on-chip approach identified a cohort of target genes including WNT1 and FOXC2, which are critically involved in cell proliferation and epithelial-to-mesenchymal transition. Also, we used flow cytometry, growth curve analysis, EdU incorporation assay, colony formation assays, trans-well invasion assays, immunohistochemical staining and in vivo bioluminescence assay to investigate the function of SIX3 in tumorigenesis. Results: We demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer. SIX3 expression is downregulated in various human cancers and high SIX3 is correlated with improved prognosis. Conclusion: Our study revealed an important mechanistic link between the loss of function of SIX3 and tumor progression, identified a molecular basis for the opposing actions of MTA1 and MTA3, and may provide new potential prognostic indicators and targets for cancer therapy.
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