title: Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells.
abstract: "Epigenetic plasticity" refers to the capability of mammalian cells to alter their differentiation status via chromatin remodeling-associated alterations in gene expression. While epigenetic plasticity has been best associated with lineage commitment of embryonic stem cells, recent studies have demonstrated chromatin remodeling even in terminally differentiated normal cells, and advanced-stage melanoma and breast cancer cells, in context-dependent responses to alterations in their microenvironment. In the current study, we extend this attribute of epigenetic plasticity to aggressive ovarian cancer cells, by using an integrative approach to associate cellular phenotypes with chromatin modifications ("ChIP-chip") and mRNA and microRNA expression. While we identified numerous gene promoters possessing the well-known "bivalent mark" of H3K27me3/H3K4me2, we also report 14 distinct, lesser-known bi-, tri-, and tetravalent combinations of activating and repressive chromatin modifications, in platinum-resistant CP70 ovarian cancer cells. The vast majority (>90%) of all the histone marks studied localized to regions within 2000 bp of transcription start sites, supporting a role in gene regulation. Upon a simple alteration in the microenvironment, transition from two- to three-dimensional culture, an increase (17% to 38%) in repressive-only marked promoters was observed, concomitant with a decrease (31% to 21%) in multivalent (i.e., juxtaposed permissive and repressive histone marked) promoters. Like embryonic/tissue stem and other (non-ovarian) carcinoma cells, ovarian cancer cell epigenetic plasticity reflects an inherent transcriptional flexibility for context-responsive alterations in phenotype. It is possible that this plasticity could be therapeutically exploited for the management of this lethal gynecologic malignancy.
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune University Campus, Pune, India. sabapat@nccs.res.in
authors.forename: Sharmila A
authors.initials: SA
authors.lastname: Bapat
authors.forename: Victor
authors.initials: V
authors.lastname: Jin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Berry
authors.forename: Curt
authors.initials: C
authors.lastname: Balch
authors.forename: Neeti
authors.initials: N
authors.lastname: Sharma
authors.forename: Nawneet
authors.initials: N
authors.lastname: Kurrey
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Xun
authors.initials: X
authors.lastname: Lan
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Brian
authors.initials: B
authors.lastname: Kennedy
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bigsby
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
mesh_terms: D042002:Chromatin Assembly and Disassembly; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; D009363:Neoplasm Proteins