Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells.
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.
Tan
Jing
J
Molecular Pharmacology, Genome Institute of Singapore, 138672, Singapore.
Yang
Xiaojing
X
Zhuang
Li
L
Jiang
Xia
X
Chen
Wei
W
Lee
Puay Leng
PL
Karuturi
R K Murthy
RK
Tan
Patrick Boon Ooi
PB
Liu
Edison T
ET
Yu
Qiang
Q
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006657:Histones; D063146:Polycomb-Group Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C048460:3-deazaneplanocin; D012319:RNA Polymerase II; D043383:Adenosylhomocysteinase; D000241:Adenosine