Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells

被引:38
作者
Bapat, Sharmila A. [5 ]
Jin, Victor [6 ]
Berry, Nicholas [1 ,5 ]
Balch, Curt [1 ,2 ,4 ]
Sharma, Neeti [5 ]
Kurrey, Nawneet [5 ]
Zhang, Shu [1 ]
Fang, Fang [1 ]
Lan, Xun [6 ]
Li, Meng [1 ]
Kennedy, Brian [6 ]
Bigsby, Robert M. [3 ,4 ]
Huang, Tim H. M. [7 ]
Nephew, Kenneth P. [1 ,2 ,3 ,4 ]
机构
[1] Indiana Univ, Sch Med, Bloomington, IN 47405 USA
[2] Indiana Univ, Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN USA
[3] Indiana Univ, Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA
[4] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA
[5] Natl Ctr Cell Sci, Pune, Maharashtra, India
[6] Ohio State Univ, Ctr Comprehens Canc, Dept Biomed Informat, Columbus, OH 43210 USA
[7] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Columbus, OH 43210 USA
关键词
histone modifications; gene expression; chromatin remodeling; ovarian cancer; epigenetic plasticity; tumor microenvironment; bivalent histone mark; EMBRYONIC STEM-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-SUPPRESSOR GENES; DNA METHYLATION; BREAST-CANCER; PHENOTYPIC PLASTICITY; SURFACE EPITHELIUM; CHROMATIN PATTERN; MIR-200; FAMILY; MAMMARY-GLAND;
D O I
10.4161/epi.5.8.13014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
"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 2,000 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 (17-38%) in repressive-only marked promoters was observed, concomitant with a decrease (31-21%) 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.
引用
收藏
页码:716 / 729
页数:14
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