title: Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2.
abstract: Platinum-based chemotherapy, with cytoreductive surgery, is the cornerstone of treatment of advanced ovarian cancer; however, acquired drug resistance is a major clinical obstacle. It has been proposed that subpopulations of tumor cells with stem cell-like properties, such as so-called side populations (SP) that overexpress ABC drug transporters, can sustain the growth of drug-resistant tumor cells, leading to tumor recurrence following chemotherapy. The histone methyltransferase EZH2 is a key component of the polycomb-repressive complex 2 required for maintenance of a stem cell state, and overexpression has been implicated in drug resistance and shorter survival of ovarian cancer patients. We observed higher percentage SP in ascites from patients that have relapsed following chemotherapy compared with chemonaive patients, consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, ABCB1 (P-glycoprotein) and EZH2 are consistently overexpressed in SP compared with non-SP from patients' tumor cells. The siRNA knockdown of EZH2 leads to loss of SP in ovarian tumor models, reduced anchorage-independent growth, and reduced tumor growth in vivo. Together, these data support a key role for EZH2 in the maintenance of a drug-resistant, tumor-sustaining subpopulation of cells in ovarian cancers undergoing chemotherapy. As such, EZH2 is an important target for anticancer drug development.
authors.affiliation: Section of Medicine, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Siân
authors.initials: S
authors.lastname: Rizzo
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Hersey
authors.forename: Paul
authors.initials: P
authors.lastname: Mellor
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santos-Silva
authors.forename: Daniel
authors.initials: D
authors.lastname: Liber
authors.forename: Louisa
authors.initials: L
authors.lastname: Luk
authors.forename: Ian
authors.initials: I
authors.lastname: Titley
authors.forename: Craig P
authors.initials: CP
authors.lastname: Carden
authors.forename: Garry
authors.initials: G
authors.lastname: Box
authors.forename: David L
authors.initials: DL
authors.lastname: Hudson
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001201:Ascites / Q000473:pathology; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology*; D063151:Polycomb Repressive Complex 2; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016190:Carboplatin; C103523:EZH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2