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

Publication ,  Journal Article
Tan, J; Yang, X; Zhuang, L; Jiang, X; Chen, W; Lee, PL; Karuturi, RKM; Tan, PBO; Liu, ET; Yu, Q
Published in: Genes Dev
May 1, 2007

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.

Duke Scholars

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Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

May 1, 2007

Volume

21

Issue

9

Start / End Page

1050 / 1063

Location

United States

Related Subject Headings

  • Repressor Proteins
  • RNA, Small Interfering
  • RNA Polymerase II
  • RNA Interference
  • Promoter Regions, Genetic
  • Polycomb-Group Proteins
  • Methylation
  • Humans
  • Histones
  • Female
 

Citation

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Tan, J., Yang, X., Zhuang, L., Jiang, X., Chen, W., Lee, P. L., … Yu, Q. (2007). Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev, 21(9), 1050–1063. https://doi.org/10.1101/gad.1524107
Tan, Jing, Xiaojing Yang, Li Zhuang, Xia Jiang, Wei Chen, Puay Leng Lee, RK Murthy Karuturi, Patrick Boon Ooi Tan, Edison T. Liu, and Qiang Yu. “Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells.Genes Dev 21, no. 9 (May 1, 2007): 1050–63. https://doi.org/10.1101/gad.1524107.
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007 May 1;21(9):1050–63.
Tan, Jing, et al. “Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells.Genes Dev, vol. 21, no. 9, May 2007, pp. 1050–63. Pubmed, doi:10.1101/gad.1524107.
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RKM, Tan PBO, Liu ET, Yu Q. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007 May 1;21(9):1050–1063.

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

May 1, 2007

Volume

21

Issue

9

Start / End Page

1050 / 1063

Location

United States

Related Subject Headings

  • Repressor Proteins
  • RNA, Small Interfering
  • RNA Polymerase II
  • RNA Interference
  • Promoter Regions, Genetic
  • Polycomb-Group Proteins
  • Methylation
  • Humans
  • Histones
  • Female