Abstract 3685: HOTAIR regulation and functionality in ovarian cancer stem cells
Year: 2019
Type: conference-abstract
Abstract: Ovarian cancer (OC) is the fifth leading cause of cancer-related death among American women. Persistence of OC stem cells (OCSCs) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse. We have previously shown that epigenetic changes in OCSCs play a role in post-therapy OCSC persistence and demonstrated that is it possible to target OCSC using epigenetic therapies. HOXC transcript antisense RNA (HOTAIR) has been shown to be associated with chemoresistance and to be overexpressed in many types of cancers, including high-grade serous OC (HGSOC). HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and due to its histone methyltransferases activity plays a key role in chromatin remodeling. Because HOTAIR is a known epigenetic regulator of differentiation and developmental genes in OC and other cancers, we hypothesize that HOTAIR is a key epigenetic regulator in OCSCs and therapeutically targeting HOTAIR in OCSCs will prevent tumor relapse. The goal of this study is to understand the role of HOTAIR in regulating OCSCs and further dissect the mechanism of action of HOTAIR in OCSCs. Aldehyde dehydrogenase (ALDH) activity and FACS was used to separate OCSCs from non-OCSCs in a panel of HGSOC cell lines (OVCAR3, CAOV3, OVCAR5, Kuramochi, COV362). Quantitative RT-PCR analysis revealed that HOTAIR was overexpressed in OCSC cells compared to non-OCSC cells. Knockout of HOTAIR using CRISPR-Cas9 system significantly decreased OCSC population and stemness-related phenotypes, including spheroid formation and colony formation ability. Overexpression of HOTAIR in HGSOC cells significantly increased these stem-like characteristics. Furthermore, targeting HOTAIR using peptide nucleic acid (PNA), which blocks interaction with Enhancer of Zeste Homologue 2 (EZH2), significantly decreased the OCSC population, indicating HOTAIR functions through EZH2 in regulating OCSCs. Combining the HOTAIR-targeting PNA with other epigenetic inhibitors, including the hypomethylating agent guadecitabine and the EZH2 inhibitor GSK503, significantly decreased proliferation and colony formation ability of HGSOC cells. We suggest that a better understanding of HOTAIR will facilitate identifying epigenomic alterations and chromatin landscape that contributes to OCSC phenotypes. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to prevent tumor relapse.Citation Format: Weini Wang, Fang Fang, Ali Ozes, Kenneth P. Nephew. HOTAIR regulation and functionality in ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3685.
Source: Tumor Biology
Authors: Weini Wang, Fang Fang, Ali Ozes, Kenneth P. Nephew
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,500
OpenAlex ID: W2953604503