Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression.
Deregulation of the pRB/E2F pathway, which occurs frequently in human malignancy, is often associated with inappropriate proliferation and/or apoptosis. While the role of E2F1 in apoptosis induction has been well-established, it remains unclear how this pro-apoptotic activity is regulated in cancer. Here we describe EZH2, an oncogenic polycomb histone methyltransferase and an E2F1 target, as an important regulator of E2F1-dependent apoptosis. We show that E2F1 induces EZH2 expression, which in turn antagonizes the induction of E2F1 pro-apoptotic target Bim expression. RNAi-mediated gene depletion of EZH2 enhances E2F1-dependent Bim expression, thereby promoting the pro-apoptotic activity of E2F1. Hence, the concomitant induction of EZH2 and Bim by E2F1 constitutes a fail-safe mechanism to allow tumor cells with aberrant E2F1 activity to evade apoptosis. These findings reveal a novel mechanism by which the apoptotic activity of E2F1 is restrained in human cancer and also provide the first evidence that EZH2 directly regulates apoptotic process in cancer cells.
Wu
Z L
ZL
Genome Institute of Singapore, Biopolis, Singapore.
Zheng
S S
SS
Li
Z M
ZM
Qiao
Y Y
YY
Aau
M Y
MY
Yu
Q
Q
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2