Browsing by Author "Ozes, Ali"

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    EZH2-mediated Downregulation of the Tumor Suppressor DAB2IP Maintains Ovarian Cancer Stem Cells
    (American Association for Cancer Research, 2020-10-15) Zong, Xingyue; Wang, Weini; Ozes, Ali; Fang, Fang; Sandusky, George E.; Nephew, Kenneth P.; Pathology and Laboratory Medicine, School of Medicine
    The majority of women diagnosed with epithelial ovarian cancer (OC) eventually develop recurrence which rapidly evolves into chemoresistant disease. Persistence of ovarian cancer stem cells (OCSC) at the end of therapy may be responsible for emergence of resistant tumors. In this study, we demonstrate that in OCSC, the tumor suppressor Disabled Homolog 2-Interacting Protein (DAB2IP) is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9-mediated deletion of DAB2IP in epithelial OC cell lines upregulated expression of stemness-related genes and induced conversion of non-CSC to CSC, while enforced expression of DAB2IP suppressed CSC properties. Transcriptomic analysis showed that overexpression of DAB2IP in OC significantly altered stemness-associated genes and bioinformatic analysis revealed WNT signaling as a dominant pathway mediating the CSC inhibitory effect of DAB2IP. Specifically, DAB2IP inhibited WNT signaling via downregulation of WNT5B, an important stemness inducer. Reverse Phase Protein Array further demonstrated activation of non-canonical WNT signaling via C-JUN as a downstream target of WNT5B, which was blocked by inhibiting RAC1, a prominent regulator of C-JUN activation. Co-administration of EZH2 inhibitor GSK126 and RAC1 inhibitor NSC23766 suppressed OCSC survival in vitro and inhibited tumor growth and increased platinum sensitivity in vivo. Overall, these data establish that DAB2IP suppresses the cancer stem cell phenotype via inhibition of WNT5B-induced activation of C-JUN and can be epigenetically silenced by EZH2 in OCSC. Targeting the EZH2/DAB2IP/C-JUN axis therefore presents a promising strategy to prevent OC recurrence and has potential for clinical translation.
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    Targeting Ovarian Cancer Stem Cells by Dual Inhibition of HOTAIR and DNA Methylation
    (American Association for Cancer Research, 2021-06) Wang, Weini; Fang, Fang; Ozes, Ali; Nephew, Kenneth P.; Medical and Molecular Genetics, School of Medicine
    Ovarian cancer is a chemoresponsive tumor with very high initial response rates to standard therapy consisting of platinum/paclitaxel. However, most women eventually develop recurrence, which rapidly evolves into chemo-resistant disease. Persistence of ovarian cancer stem cells (OCSC) at the end of therapy has been shown to contribute to resistant tumors. In this study, we demonstrate that the long non-coding RNA HOTAIR is overexpressed in HGSOC cell lines. Furthermore, HOTAIR expression was upregulated in OCSC compared to non-CSC, ectopic overexpression of HOTAIR enriched the ALDH+ cell population and HOTAIR overexpression increased spheroid formation and colony forming ability. Targeting HOTAIR using peptide nucleic acid-PNA3®, which acts by disrupting the interaction between HOTAIR and EZH2, in combination with a DNMT inhibitor inhibited OCSC spheroid formation and decreased the percentage of ALDH+ cells. Disrupting HOTAIR-EZH2 with PNA3® in combination with the DNMTi on the ability of OCSC to initiate tumors in vivo as xenografts was examined. HGSOC OVCAR3 cells were treated with PNA3® in vitro and then implanted in nude mice. Tumor growth, initiation and stem cell frequency were inhibited. Collectively, these results demonstrate that blocking HOTAIR-EZH2 interaction combined with inhibiting DNA methylation is a potential approach to eradicate OCSCs and block disease recurrence.