GATA3 as a master regulator and therapeutic target in ovarian high-grade serous carcinoma stem cells.
Hsiang-Ju ChenRui-Lan HuangPhui-Ly LiewPo-Hsuan SuLin-Yu ChenYu-Chun WengCheng-Chang ChangYu-Chi WangMichael Wing-Yan ChanHung Cheng LaiPublished in: International journal of cancer (2018)
Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells. GATA3 expression associates with poor prognosis of ovarian HGSC patients, and was found to recruit the histone H3, lysine 27 (H3K27) demethylase, UTX, activate stemness markers, and promote stem-like phenotypes in ovarian HGSC cell lines. Targeting UTX by its inhibitor, GSKJ4, impeded GATA3-driven stemness phenotypes, and enhanced apoptosis of GATA3-expressing cancer cells. Combinations of gemcitabine or paclitaxel with GSKJ4, resulted in a synergistic cytotoxic effect. Our findings provide evidence for a new role for GATA3 in ovarian HGSC stemness, and demonstrate that GATA3 may serve as a biomarker for precision epigenetic therapy in the future.
Keyphrases
- transcription factor
- high grade
- stem cells
- poor prognosis
- low grade
- cancer stem cells
- dna binding
- epithelial mesenchymal transition
- long non coding rna
- oxidative stress
- cell therapy
- dna methylation
- cancer therapy
- gene expression
- end stage renal disease
- newly diagnosed
- drug delivery
- ejection fraction
- young adults
- signaling pathway
- peritoneal dialysis
- amino acid
- papillary thyroid
- prognostic factors
- locally advanced
- bone marrow
- squamous cell
- replacement therapy