GATA3 as a master regulator and therapeutic target in ovarian high‐grade serous carcinoma stem cells

Abstract

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.

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

“…EMT is associated with malignant stem cell function, and previous studies indicate that cancer stem cells (CSCs) are involved in tumor metastasis and relapse . To determine whether P2X7 affected stemness of osteosarcoma cells, we sorted CSCs from osteosarcoma cell lines using flow cytometry and treated them with BzATP or A740003.…”

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse . Cells undergoing EMT are known to acquire stem cell‐like properties.…”

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse. 34,[47][48][49][50] Cells undergoing EMT are known to acquire stem cell-like properties. Loss of epithelial marker E-cadherin, increased expression of mesenchymal markers Fibronectin and Vimentin and the EMT regulator Snail, which are important events in EMT.…”

“…EMT is associated with malignant stem cell function, 30 and previous studies indicate that cancer stem cells (CSCs) are involved in tumor metastasis and relapse. [31][32][33][34] To determine whether P2X7 affected stemness of osteosarcoma cells, we sorted CSCs from osteosarcoma cell lines using flow cytometry and treated them with BzATP or A740003. 15% to 50% more CD133 high CSCs were detected in 5 to 125 μM BzATP treated HOS/MNNG cells, but inhibition of P2X7 using an antagonist or shRNA decreased CD133 high CSCs by 50%.…”

NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer

“…In the female reproductive system, ovarian cancer (OC) is the most fatal cancer 1 . Although platinum‐based chemotherapy has improved patient survival over the past 30 years, most patients with advanced OC experience recurrence and develop a drug‐resistant disease.…”