Browsing by Subject "HOTAIR"

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    Elevated expression of long intergenic non-coding RNA HOTAIR in a basal-like variant of MCF-7 breast cancer cells
    (Wiley, 2015-12) Zhuang, Yan; Nguyen, Hong T.; Burow, Matthew E.; Zhuo, Ying; El-Dahr, Samir S.; Yao, Xiao; Cao, Subing; Flemington, Erik K.; Nephew, Kenneth P.; Fang, Fang; Collins-Burow, Bridgette; Rhodes, Lyndsay V.; Yu, Qiang; Jayawickramarajah, Janarthanan; Shan, Bin; Department of Medicine, IU School of Medicine
    Epigenetic regulation of gene expression is critical to phenotypic maintenance and transition of human breast cancer cells. HOX antisense intergenic RNA (HOTAIR) is a long intergenic non-coding RNA that epigenetically represses gene expression via recruitment of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase. Elevated expression of HOTAIR promotes progression of breast cancer. In the current study we examined the expression and function of HOTAIR in MCF-7-TNR cells, a derivative of the luminal-like breast cancer cell line MCF-7 that acquired resistance to TNF-α-induced cell death. The expression of HOTAIR, markers of the luminal-like and basal-like subtypes, and growth were compared between MCF-7 and MCF-7-TNR cells. These variables were further assessed upon inhibition of HOTAIR, EZH2, p38 MAPK, and SRC kinase in MCF-7-TNR cells. When compared with MCF-7 cells, MCF-7-TNR cells exhibited an increase in the expression of HOTAIR, which correlated with characteristics of a luminal-like to basal-like transition as evidenced by dysregulated gene expression and accelerated growth. MCF-7-TNR cells exhibited reduced suppressive histone H3 lysine27 trimethylation on the HOTAIR promoter. Inhibition of HOTAIR and EZH2 attenuated the luminal-like to basal-like transition in terms of gene expression and growth in MCF-7-TNR cells. Inhibition of p38 and SRC diminished HOTAIR expression and the basal-like phenotype in MCF-7-TNR cells. HOTAIR was robustly expressed in the native basal-like breast cancer cells and inhibition of HOTAIR reduced the basal-like gene expression and growth. Our findings suggest HOTAIR-mediated regulation of gene expression and growth associated with the basal-like phenotype of breast cancer cells.
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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.