Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells.

By Jing Tan, Xiaojing Yang, Zhuangwu Li, Xia Jiang, Wei Chen, Puay Leng Lee, R. Karuturi, P. Tan, E. Liu, Qiang Yu. Genes & Development, 2007

917 citations recorded by the source corpus.

Polycomb-repressive complex 2 (PRC2)-mediated histone methylation plays an important role in aberrant cancer gene silencing and is a potential target for cancer therapy. Here we show that S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) induces efficient apoptotic cell death in cancer cells but not in normal cells. We found that DZNep effectively depleted cellular levels of PRC2 components EZH2, SUZ12, and EED and inhibited associated histone H3 Lys 27 methylation (but not H3 Lys 9 methylation). By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin immunoprecipitation (ChIP) studies, we have identified a prominent set of genes selectively repressed by PRC2 in breast cancer that can be reactivated by DZNep. We further demonstrate that the preferential reactivation of a set of these genes by DZNep, including a novel apoptosis affector, FBXO32, contributes to DZNep-induced apoptosis in breast cancer cells. Our results demonstrate the unique feature of DZNep as a novel chromatin remodeling compound and suggest that pharmacologic reversal of PRC2-mediated gene repression by DZNep may constitute a novel approach for cancer therapy.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e644574db00590b383e0f4d7acfd0d9c1b804c9a

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Citations in the corpus

Cancer epigenetics reaches mainstream oncology (2011, background): “DZNep induces apoptosis in breast cancer MCF7 and colorectal HCT116 cells, where it promotes the depletion of the polycomb-repressive complex-2 proteins (for instance, EZH2) and inhibits methylation of the H3K27 modificatio”
Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells (2013, methodology): “GSC-derived xenograft tumors were treated with DZNep (1 mg/kg body weight twice a week via intraperitoneal injection) for 2 weeks, harvested, and processed for immunoblots and co-IP analysis (I) and (J) and IF staining (K).”
Epigenetic Modifications as Therapeutic Targets (2010, background): “DZNep depletes cellular levels of PRC2 components (EZH2, EED and SUZ12) and consequently reduces H3K27me3 levels and induces apoptosis in breast cancer, but not normal, cell”
Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. (2011, neutral): “Biotinylated peptides, H3 (1-21) (#12-403), H3 (21-44) (#12-404), H3(21-44)K27(me1) (#12-567), H3(21-44)K27(me2) (#12566), and H3(21-44)K27(me3) (#12-565), were purchased from Upstate Biotechnology.”
Repression of E-cadherin by the polycomb group protein EZH2 in cancer (2008, background): “, 2005), as well as in vitro cancer cell lines such as SKBR3, MDA-MB-231, T47D breast cell lines (Tan et al., 2007) and the prostate cell lines DU145 and LNCaP (Beke et al.”