Objectives The objective of this study is to explore the role of SOX4 in ovarian cancer stem cells (OCSCs) and elucidate the underlying mechanisms.
Methods Ovarian cancer cell lines and primary cells were used in this study. Lentivirus system was used for genetic manipulation. Sphere-forming activity was examined by sphere formation assay. limiting dilution assay was employed to determine the frequency of sphere-forming cell. The mRNA and protein levels were determined by qRT-PCR and western blot, respectively. The effect of SOX4 on the transcriptional activity of HDAC1 promoter was tested by luciferase assay and their direct binding was determined by Chromatin immunoprecipitation (ChIP) assay. The protein levels of surface markers were examined by flowcytometry.
Results SOX4 overexpression significantly increased the sphere-forming activities, the frequency of sphere-forming cells and the expression levels of OCSCs markers in OCSCs; SOX4 depletion led to opposite results. SOX4 directly bound to the HDAC1 promoter and increased the transcriptional activities of HDAC1 promoter and there are four SOX4-bidning sites in HDAC1 promotor. HDAC1 predicts poor prognosis of ovarian cancer and positively regulates OCSCs stemness. HDAC1 ablation abolished the effect of SOX4 on OCSCs stemness.
Conclusions The results in this study demonstrated a novel mechanism that SOX4 promotes ovarian cancer stemness by transcriptionally activating HDAC1. This finding suggests that HDAC1 inhibitor could be an effective therapeutic agent for eradicating human OCSCs driven by aberrant SOX4 upregulation.
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