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

Hsiang Ju Chen, Rui Lan Huang, Phui Ly Liew, Po Hsuan Su, Lin Yu Chen, Yu Chun Weng, Cheng Chang Chang, Yu Chi Wang, Michael Wing Yan Chan, Hung Cheng Lai

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusAccepted/In press - Jan 1 2018

Keywords

  • cancer stem cells
  • GATA3
  • GSKJ4
  • ovarian cancer
  • UTX

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Chen, H. J., Huang, R. L., Liew, P. L., Su, P. H., Chen, L. Y., Weng, Y. C., Chang, C. C., Wang, Y. C., Chan, M. W. Y., & Lai, H. C. (Accepted/In press). GATA3 as a master regulator and therapeutic target in ovarian high-grade serous carcinoma stem cells. International Journal of Cancer. https://doi.org/10.1002/ijc.31750