Activated p53 suppresses the histone methyltransferase EZH2 gene.
Replicative senescence is an irreversible cell cycle arrest that limits the proliferation of damaged cells and may be an important tumor suppression mechanism in vivo. This process is regulated at critical steps by the tumor suppressor p53. To identify genes that may regulate the senescence process, we performed cDNA microarray analysis of gene expression in senescent, young proliferating, and hTERT-immortalized primary human fibroblasts. The histone methyltransferase (HMTase), EZH2, was specifically downregulated in senescent cells. Activated p53 suppressed EZH2 gene expression through repression of the EZH2 gene promoter. This activity of p53 requires intact p53 transactivation and DNA binding domains. Furthermore, the repression of EZH2 promoter by p53 is dependent on p53 transcriptional target p21(Waf1) inactivating RB/E2F pathways. In addition, the knockdown of EZH2 expression retards cell proliferation and induces G2/M arrest. We suggest that the p53-dependent suppression of EZH2 expression is a novel pathway that contributes to p53-mediated G2/M arrest. EZH2 associated complex possesses HMTase activity and is involved in epigenetic regulation. Activated p53 suppresses EZH2 expression, suggesting a further role for p53 in epigenetic regulation and in the maintenance of genetic stability. Suppression of EZH2 expression in tumors by p53 may lead to novel approaches to control cancer progression.
Tang
Xiaohu
X
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Milyavsky
Michael
M
Shats
Igor
I
Erez
Neta
N
Goldfinger
Naomi
N
Rotter
Varda
V
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D016195:G2 Phase / Q000235:genetics; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000235:genetics; D008969:Molecular Sequence Data; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D011496:Protein Methyltransferases; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D019098:Telomerase