Browsing by Author "Zong, Xingyue"

Now showing 1 - 6 of 6
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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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    IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells
    (American Society for Clinical Investigation, 2018-12-06) Wang, Yinu; Zong, Xingyue; Mitra, Sumegha; Mitra, Anirban Kumar; Matei, Daniela; Nephew, Kenneth P.; Medical and Molecular Genetics, School of Medicine
    In high-grade serous ovarian cancer (OC), chemotherapy eliminates the majority of tumor cells, leaving behind residual tumors enriched in OC stem cells (OCSC). OCSC, defined as aldehyde dehydrogenase–positive (ALDH+), persist and contribute to tumor relapse. Inflammatory cytokine IL-6 is elevated in residual tumors after platinum treatment, and we hypothesized that IL-6 plays a critical role in platinum-induced OCSC enrichment. We demonstrate that IL-6 regulates stemness features of OCSC driven by ALDH1A1 expression and activity. We show that platinum induces IL-6 secretion by cancer-associated fibroblasts in the tumor microenvironment, promoting OCSC enrichment in residual tumors after chemotherapy. By activating STAT3 and upregulating ALDH1A1 expression, IL-6 treatment converted non-OCSC to OCSC. Having previously shown altered DNA methylation in OCSC, we show here that IL-6 induces DNA methyltransferase 1 (DNMT1) expression and the hypomethylating agent (HMA) guadecitabine induced differentiation of OCSC and reduced — but did not completely eradicate — OCSC. IL-6 neutralizing antibody (IL-6-Nab) combined with HMA fully eradicated OCSC, and the combination blocked IL-6/IL6-R/pSTAT3–mediated ALDH1A1 expression and eliminated OCSC in residual tumors that persisted in vivo after chemotherapy. We conclude that IL-6 signaling blockade combined with an HMA can eliminate OCSC after platinum treatment, supporting this strategy to prevent tumor recurrence after standard chemotherapy.
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    Ovarian Cancer Stem Cells: Role in Metastasis and Opportunity for Therapeutic Targeting
    (MDPI, 2019-07-03) Zong, Xingyue; Nephew, Kenneth P.; Cellular and Integrative Physiology, School of Medicine
    Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Cancer stem cells (CSCs) that exist within the bulk tumor survive first-line chemotherapy and contribute to resistant disease with metastasis. Understanding the key features of CSC biology provides valuable opportunities to develop OCSC-directed therapeutics, which will eventually improve the clinical outcomes of patients. Although significant developments have occurred since OCSCs were first described, the involvement of CSCs in ovarian tumor metastasis is not fully understood. Here, we discuss putative CSC markers and the fundamental role of CSCs in facilitating tumor dissemination in OC. Additionally, we focus on promising CSC-targeting strategies in preclinical and clinical studies of OC and discuss potential challenges in CSC research.
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    Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS
    (Nature Publishing Group, 2020-09-21) Wu, Xue; Niculite, Cristina M.; Preda, Mihai Bogdan; Rossi, Annalisa; Tebaldi, Toma; Butoi, Elena; White, Mattie K.; Tudoran, Oana M.; Petrusca, Daniela N.; Jannasch, Amber S.; Bone, William P.; Zong, Xingyue; Fang, Fang; Burlacu, Alexandrina; Paulsen, Michelle T.; Hancock, Brad A.; Sandusky, George E.; Mitra, Sumegha; Fishel, Melissa L.; Buechlein, Aaron; Ivan, Cristina; Oikonomopoulos, Spyros; Gorospe, Myriam; Mosley, Amber; Radovich, Milan; Davé, Utpal P.; Ragoussis, Jiannis; Nephew, Kenneth P.; Mari, Bernard; McIntyre, Alan; Konig, Heiko; Ljungman, Mats; Cousminer, Diana L.; Macchi, Paolo; Ivan, Mircea; Medicine, School of Medicine
    We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.
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    Single-cell analysis of a high-grade serous ovarian cancer cell line reveals transcriptomic changes and cell subpopulations sensitive to epigenetic combination treatment
    (Public Library of Science, 2022-08-03) Sriramkumar, Shruthi; Metcalfe, Tara X.; Lai, Tim; Zong, Xingyue; Fang, Fang; O'Hagan, Heather M.; Nephew, Kenneth M.; Medical and Molecular Genetics, School of Medicine
    Ovarian cancer (OC) is a lethal gynecological malignancy with a five-year survival rate of only 46%. Development of resistance to platinum-based chemotherapy is a common cause of high mortality rates among OC patients. Tumor and transcriptomic heterogeneity are drivers of platinum resistance in OC. Platinum-based chemotherapy enriches for ovarian cancer stem cells (OCSCs) that are chemoresistant and contribute to disease recurrence and relapse. Studies examining the effect of different treatments on subpopulations of HGSOC cell lines are limited. Having previously demonstrated that combined treatment with an enhancer of zeste homolog 2 inhibitor (EZH2i) and a RAC1 GTPase inhibitor (RAC1i) inhibited survival of OCSCs, we investigated EZH2i and RAC1i combination effects on HGSOC heterogeneity using single cell RNA sequencing. We demonstrated that RAC1i reduced expression of stemness and early secretory marker genes, increased expression of an intermediate secretory marker gene and induced inflammatory gene expression. Importantly, RAC1i alone and in combination with EZH2i significantly reduced oxidative phosphorylation and upregulated Sirtuin signaling pathways. Altogether, we demonstrated that combining a RAC1i with an EZH2i promoted differentiation of subpopulations of HGSOC cells, supporting the future development of epigenetic drug combinations as therapeutic approaches in OC.
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    Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and breast cancer
    (SpringerNature, 2017-04-18) Özeş, Ali R.; Wang, Yinu; Zong, Xingyue; Fang, Fang; Pilrose, Jay; Nephew, Kenneth P.; Department of Obstetrics and Gynecology, School of Medicine
    Long non-coding RNAs (lncRNAs) play key roles in human diseases, including cancer. Functional studies of the lncRNA HOTAIR (HOX transcript antisense RNA) provide compelling evidence for therapeutic targeting of HOTAIR in cancer, but targeting lncRNAs in vivo has proven to be difficult. In the current study, we describe a peptide nucleic acids (PNA)-based approach to block the ability of HOTAIR to interact with EZH2 and subsequently inhibit HOTAIR-EZH2 activity and resensitize resistant ovarian tumors to platinum. Treatment of HOTAIR-overexpressing ovarian and breast cancer cell lines with PNAs decreased invasion and increased chemotherapy sensitivity. Furthermore, the mechanism of action correlated with reduced nuclear factor-kappaB (NF-κB) activation and decreased expression of NF-κB target genes matrix metalloprotease 9 and interleukin 6. To deliver the anti-lncRNA to the acidic (pH approximately 6) tumor microenvironment, PNAs were conjugated to pH-low insertion peptide (pHLIP). Treatment of mice harboring platinum-resistant ovarian tumor xenografts with pHLIP-PNA constructs suppressed HOTAIR activity, reduced tumor formation and improved survival. This first report on pHLIP-PNA lncRNA targeting solid tumors in vivo suggests a novel cancer therapeutic approach.