Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 310 (5746): 306-310

Copyright © 2005 by the American Association for the Advancement of Science

Akt-Mediated Phosphorylation of EZH2 Suppresses Methylation of Lysine 27 in Histone H3

Tai-Lung Cha,1,2* Binhua P. Zhou,1{dagger} Weiya Xia,1 Yadi Wu,1 Cheng-Chieh Yang,1,2 Chun-Te Chen,1 Bo Ping,1 Arie P. Otte,3 Mien-Chie Hung1,2{ddagger}

Abstract: Enhancer of Zeste homolog 2 (EZH2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone H3. Here, we show that Akt phosphorylates EZH2 at serine 21 and suppresses its methyltransferase activity by impeding EZH2 binding to histone H3, which results in a decrease of lysine 27 trimethylation and derepression of silenced genes. Our results imply that Akt regulates the methylation activity, through phosphorylation of EZH2, which may contribute to oncogenesis.

1 Department of Molecular and Cellular Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
2 Graduate School of Biomedical Sciences, the University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
3 Swammerdam Institute for Life Sciences, University of Amsterdam, Kruislaan 406, 1098 SM Amsterdam, the Netherlands.

* Present address: Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, National Defense University, Taipei, 104, Taiwan.

{dagger} Present address: Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, TX 77555–1048, USA.

{ddagger} To whom correspondence should be addressed. E-mail: mhung{at}mdanderson.org

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Proteomics in epigenetics: new perspectives for cancer research.
T. Bartke, J. Borgel, and P. A. DiMaggio (2013)
Briefings in Functional Genomics 12, 205-218
   Abstract »    Full Text »    PDF »
MYC Acts via the PTEN Tumor Suppressor to Elicit Autoregulation and Genome-Wide Gene Repression by Activation of the Ezh2 Methyltransferase.
M. Kaur and M. D. Cole (2013)
Cancer Res. 73, 695-705
   Abstract »    Full Text »    PDF »
NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes.
N. Minnebo, J. Gornemann, N. O'Connell, N. Van Dessel, R. Derua, M. W. Vermunt, R. Page, M. Beullens, W. Peti, A. Van Eynde, et al. (2013)
Nucleic Acids Res. 41, 842-854
   Abstract »    Full Text »    PDF »
EZH2 Goes Solo.
G. Cavalli (2012)
Science 338, 1430-1431
   Abstract »    Full Text »    PDF »
EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent.
K. Xu, Z. J. Wu, A. C. Groner, H. H. He, C. Cai, R. T. Lis, X. Wu, E. C. Stack, M. Loda, T. Liu, et al. (2012)
Science 338, 1465-1469
   Abstract »    Full Text »    PDF »
Oncogene Ras/Phosphatidylinositol 3-Kinase Signaling Targets Histone H3 Acetylation at Lysine 56.
Y. Liu, D.-L. Wang, S. Chen, L. Zhao, and F.-L. Sun (2012)
J. Biol. Chem. 287, 41469-41480
   Abstract »    Full Text »    PDF »
Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus.
Y. Liu, F. Liu, H. Yu, X. Zhao, G. Sashida, A. Deblasio, M. Harr, Q.-B. She, Z. Chen, H.-K. Lin, et al. (2012)
Science Signaling 5, ra77
   Abstract »    Full Text »    PDF »
Collaboration of Kras and Androgen Receptor Signaling Stimulates EZH2 Expression and Tumor-Propagating Cells in Prostate Cancer.
H. Cai, S. Memarzadeh, T. Stoyanova, Z. Beharry, A. S. Kraft, and O. N. Witte (2012)
Cancer Res. 72, 4672-4681
   Abstract »    Full Text »    PDF »
Posttranslational regulation of self-renewal capacity: insights from proteome and phosphoproteome analyses of stem cell leukemia.
M. Trost, M. Sauvageau, O. Herault, P. Deleris, C. Pomies, J. Chagraoui, N. Mayotte, S. Meloche, G. Sauvageau, and P. Thibault (2012)
Blood 120, e17-e27
   Abstract »    Full Text »    PDF »
Regulation of A Disintegrin And Metalloprotease-33 Expression by Transforming Growth Factor-{beta}.
Y. Yang, J. Wicks, H. M. Haitchi, R. M. Powell, W. Manuyakorn, P. H. Howarth, S. T. Holgate, and D. E. Davies (2012)
46, 633-640
   Abstract »    Full Text »    PDF »
Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis.
K. L. Greathouse, T. Bredfeldt, J. I. Everitt, K. Lin, T. Berry, K. Kannan, M. L. Mittelstadt, S.-m. Ho, and C. L. Walker (2012)
Mol. Cancer Res. 10, 546-557
   Abstract »    Full Text »    PDF »
Akt and ERK Control the Proliferative Response of Mammary Epithelial Cells to the Growth Factors IGF-1 and EGF Through the Cell Cycle Inhibitor p57Kip2.
D. T. Worster, T. Schmelzle, N. L. Solimini, E. S. Lightcap, B. Millard, G. B. Mills, J. S. Brugge, and J. G. Albeck (2012)
Science Signaling 5, ra19
   Abstract »    Full Text »    PDF »
When Silence is Broken: Polycomb Group Proteins in Heart Development.
G. Dobreva and T. Braun (2012)
Circ. Res. 110, 372-374
   Full Text »    PDF »
Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes.
P. L. Hyland, S. S. McDade, R. McCloskey, G. J. Dickson, K. Arthur, D. J. McCance, and D. Patel (2011)
J. Virol. 85, 10999-11006
   Abstract »    Full Text »    PDF »
Cyclin-dependent Kinase 1 (CDK1)-mediated Phosphorylation of Enhancer of Zeste 2 (Ezh2) Regulates Its Stability.
S. C. Wu and Y. Zhang (2011)
J. Biol. Chem. 286, 28511-28519
   Abstract »    Full Text »    PDF »
Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells.
W.-C. Huang, Y.-J. Chen, L.-Y. Li, Y.-L. Wei, S.-C. Hsu, S.-L. Tsai, P.-C. Chiu, W.-P. Huang, Y.-N. Wang, C.-H. Chen, et al. (2011)
J. Biol. Chem. 286, 20558-20568
   Abstract »    Full Text »    PDF »
Lung-Cancer Chemoprevention by Induction of Synthetic Lethality in Mutant KRAS Premalignant Cells In Vitro and In Vivo.
S. Huang, X. Ren, L. Wang, L. Zhang, and X. Wu (2011)
Cancer Prevention Research 4, 666-673
   Abstract »    Full Text »    PDF »
Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy.
D. Sasaki, Y. Imaizumi, H. Hasegawa, A. Osaka, K. Tsukasaki, Y. L. Choi, H. Mano, V. E. Marquez, T. Hayashi, K. Yanagihara, et al. (2011)
Haematologica 96, 712-719
   Abstract »    Full Text »    PDF »
Chromatin in the Nuclear Landscape.
D. B. Beck, R. Bonasio, S. Kaneko, G. Li, G. Li, R. Margueron, H. Oda, K. Sarma, R. J. Sims III, J. Son, et al. (2011)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
DNA hypermethylation profiles associated with glioma subtypes and EZH2 and IGFBP2 mRNA expression.
S. Zheng, E. A. Houseman, Z. Morrison, M. R. Wrensch, J. S. Patoka, C. Ramos, D. A. Haas-Kogan, S. McBride, C. J. Marsit, B. C. Christensen, et al. (2011)
Neuro Oncology 13, 280-289
   Abstract »    Full Text »    PDF »
Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer.
T. Zuo, T.-M. Liu, X. Lan, Y.-I. Weng, R. Shen, F. Gu, Y.-W. Huang, S. Liyanarachchi, D. E. Deatherage, P.-Y. Hsu, et al. (2011)
Cancer Res. 71, 1752-1762
   Abstract »    Full Text »    PDF »
Rapid activation of the bivalent gene Sox21 requires displacement of multiple layers of gene-silencing machinery.
H. Chakravarthy, B. D. Ormsbee, S. K. Mallanna, and A. Rizzino (2011)
FASEB J 25, 206-218
   Abstract »    Full Text »    PDF »
Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA.
S. Kaneko, G. Li, J. Son, C.-F. Xu, R. Margueron, T. A. Neubert, and D. Reinberg (2010)
Genes & Dev. 24, 2615-2620
   Abstract »    Full Text »    PDF »
The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets.
N. Van Dessel, L. Beke, J. Gornemann, N. Minnebo, M. Beullens, N. Tanuma, H. Shima, A. Van Eynde, and M. Bollen (2010)
Nucleic Acids Res. 38, 7500-7512
   Abstract »    Full Text »    PDF »
The T-loop Extension of the Tomato Protein Kinase AvrPto-dependent Pto-interacting Protein 3 (Adi3) Directs Nuclear Localization for Suppression of Plant Cell Death.
M. J. Ek-Ramos, J. Avila, C. Cheng, G. B. Martin, and T. P. Devarenne (2010)
J. Biol. Chem. 285, 17584-17594
   Abstract »    Full Text »    PDF »
Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications.
M. J. Kwon, S.-S. Kim, Y.-L. Choi, H. S. Jung, C. Balch, S.-H. Kim, Y.-S. Song, V. E. Marquez, K. P. Nephew, and Y. K. Shin (2010)
Carcinogenesis 31, 974-983
   Abstract »    Full Text »    PDF »
Xenoestrogen-Induced Regulation of EZH2 and Histone Methylation via Estrogen Receptor Signaling to PI3K/AKT.
T. G. Bredfeldt, K. L. Greathouse, S. H. Safe, M. C. Hung, M. T. Bedford, and C. L. Walker (2010)
Mol. Endocrinol. 24, 993-1006
   Abstract »    Full Text »    PDF »
Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma.
B. M. Costa, J. S. Smith, Y. Chen, J. Chen, H. S. Phillips, K. D. Aldape, G. Zardo, J. Nigro, C. D. James, J. Fridlyand, et al. (2010)
Cancer Res. 70, 453-462
   Abstract »    Full Text »    PDF »
Hyperactivated NF-{kappa}B and AP-1 Transcription Factors Promote Highly Accessible Chromatin and Constitutive Transcription across the Interleukin-6 Gene Promoter in Metastatic Breast Cancer Cells.
M. N. Ndlovu, C. Van Lint, K. Van Wesemael, P. Callebert, D. Chalbos, G. Haegeman, and W. Vanden Berghe (2009)
Mol. Cell. Biol. 29, 5488-5504
   Abstract »    Full Text »    PDF »
Polycomb Group Protein Enhancer of Zeste 2 Is an Oncogene That Promotes the Neoplastic Transformation of a Benign Prostatic Epithelial Cell Line.
B. D.W. Karanikolas, M. L. Figueiredo, and L. Wu (2009)
Mol. Cancer Res. 7, 1456-1465
   Abstract »    Full Text »    PDF »
Alterations of histone modifications by cobalt compounds.
Q. Li, Q. Ke, and M. Costa (2009)
Carcinogenesis 30, 1243-1251
   Abstract »    Full Text »    PDF »
Arsenite alters global histone H3 methylation.
X. Zhou, H. Sun, T. P. Ellen, H. Chen, and M. Costa (2008)
Carcinogenesis 29, 1831-1836
   Abstract »    Full Text »    PDF »
Regulators of Cellular Levels of Histone Acetylation in Saccharomyces cerevisiae.
W. Peng, C. Togawa, K. Zhang, and S. K. Kurdistani (2008)
Genetics 179, 277-289
   Abstract »    Full Text »    PDF »
New insights into PTEN.
T. Tamguney and D. Stokoe (2007)
J. Cell Sci. 120, 4071-4079
   Abstract »    Full Text »    PDF »
PRDM5 Identified as a Target of Epigenetic Silencing in Colorectal and Gastric Cancer.
Y. Watanabe, M. Toyota, Y. Kondo, H. Suzuki, T. Imai, M. Ohe-Toyota, R. Maruyama, M. Nojima, Y. Sasaki, Y. Sekido, et al. (2007)
Clin. Cancer Res. 13, 4786-4794
   Abstract »    Full Text »    PDF »
Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1.
K. Higashimoto, P. Kuhn, D. Desai, X. Cheng, and W. Xu (2007)
PNAS 104, 12318-12323
   Abstract »    Full Text »    PDF »
Gene Alterations Identified by Expression Profiling in Tumor-Associated Endothelial Cells from Invasive Ovarian Carcinoma.
C. Lu, T. Bonome, Y. Li, A. A. Kamat, L. Y. Han, R. Schmandt, R. L. Coleman, D. M. Gershenson, R. B. Jaffe, M. J. Birrer, et al. (2007)
Cancer Res. 67, 1757-1768
   Abstract »    Full Text »    PDF »
Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases.
M. A. Bogoyevitch and B. Kobe (2006)
Microbiol. Mol. Biol. Rev. 70, 1061-1095
   Abstract »    Full Text »    PDF »
Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells.
W. Fiskus, M. Pranpat, M. Balasis, B. Herger, R. Rao, A. Chinnaiyan, P. Atadja, and K. Bhalla (2006)
Mol. Cancer Ther. 5, 3096-3104
   Abstract »    Full Text »    PDF »
Systems Biology of AGC Kinases in Fungi.
A. Sobko (2006)
Sci. STKE 2006, re9
   Abstract »    Full Text »    PDF »
Dominant-Negative Histone H3 Lysine 27 Mutant Derepresses Silenced Tumor Suppressor Genes and Reverses the Drug-Resistant Phenotype in Cancer Cells.
P. H. Abbosh, J. S. Montgomery, J. A. Starkey, M. Novotny, E. G. Zuhowski, M. J. Egorin, A. P. Moseman, A. Golas, K. M. Brannon, C. Balch, et al. (2006)
Cancer Res. 66, 5582-5591
   Abstract »    Full Text »    PDF »
Wnt signaling: is the party in the nucleus?.
K. Willert and K. A. Jones (2006)
Genes & Dev. 20, 1394-1404
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882