The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.

The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.

Theranostics. 2018;8(4):972-989

Authors: Zheng Y, Zeng Y, Qiu R, Liu R, Huang W, Hou Y, Wang S, Leng S, Feng D, Yang Y, Wang Y

Abstract 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.

PMID: 29463994 [PubMed - in process]