Single-cell analysis of a high-grade serous ovarian cancer cell line reveals transcriptomic changes and cell subpopulations sensitive to epigenetic combination treatment.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Cystadenocarcinoma, Serous*/genetics ; Ovarian Neoplasms*/drug therapy ; Ovarian Neoplasms*/genetics ; Ovarian Neoplasms*/pathology; Carcinoma, Ovarian Epithelial/genetics ; Cell Line ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic ; Female ; Humans ; Neoplasm Recurrence, Local/genetics ; Platinum/therapeutic use ; Single-Cell Analysis ; Transcriptome
    • Abstract:
      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.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Grant Information:
      P30 CA082709 United States CA NCI NIH HHS
    • Accession Number:
      49DFR088MY (Platinum)
    • Publication Date:
      Date Created: 20220803 Date Completed: 20220805 Latest Revision: 20220825
    • Publication Date:
      20240829
    • Accession Number:
      PMC9348737
    • Accession Number:
      10.1371/journal.pone.0271584
    • Accession Number:
      35921335