TET2 binds the androgen receptor and loss is associated with prostate cancer

被引：53

作者：

Nickerson, M. L. ^{[1
,8
]}

Das, S. ^{[2
]}

Im, K. M. ^{[3
]}

Turan, S. ^{[1
]}

Berndt, S. I. ^{[4
]}

Li, H. ^{[1
,5
]}

Lou, H. ^{[1
,5
]}

Brodie, S. A. ^{[4
,6
]}

Billaud, J. N. ^{[7
]}

Zhang, T. ^{[8
]}

Bouk, A. J. ^{[4
]}

Butcher, D. ^{[9
]}

Wang, Z. ^{[4
]}

Sun, L. ^{[10
]}

Misner, K. ^{[1
]}

Tan, W. ^{[1
]}

Esnakula, A. ^{[11
]}

Esposito, D. ^{[12
]}

Huang, W. Y. ^{[4
]}

Hoover, R. N. ^{[4
]}

Tucker, M. A. ^{[4
]}

Keller, J. R. ^{[10
]}

Boland, J. ^{[4
,6
]}

Brown, K. ^{[8
]}

Anderson, S. K. ^{[1
]}

Moore, L. E. ^{[4
]}

Isaacs, W. B. ^{[13
]}

Chanock, S. J. ^{[4
]}

Yeager, M. ^{[4
,6
]}

Dean, M. ^{[1
,8
]}

Andresson, T. ^{[2
]}

机构：

[1] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA

[2] Leidos Biomed Res Inc, Prot Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA

[3] Data Sci Genom, Ellicott City, MD USA

[4] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[5] Leidos Biomed Res Inc, Basic Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA

[6] Leidos Biomed Res Inc, Canc Genom Res, Frederick Natl Lab Canc Res, Frederick, MD USA

[7] Ingenu Syst Inc, Redwood City, CA USA

[8] NCI, Lab Translat Genom, 8717 Grovemont Circle,Rm 225C, Bethesda, MD 20892 USA

[9] Leidos Biomed Res Inc, Pathol & Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA

[10] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA

[11] Howard Univ, Coll Med, Dept Pathol, Howard Univ Hosp, Washington, DC USA

[12] Leidos Biomed Res Inc, Prot Express Lab, Frederick Natl Lab Canc Res, Frederick, MD USA

[13] Johns Hopkins Univ, Sch Med, Baltimore, MD USA

来源：

ONCOGENE | 2017年 / 36卷 / 15期

基金：

美国国家卫生研究院;

关键词：

GENE; MUTATIONS; LANDSCAPE; HYDROXYMETHYLATION; IDENTIFICATION; HOMEODOMAIN; PREDICTION; INSIGHT; GENOME;

D O I：

10.1038/onc.2016.376

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression are positively correlated in prostate tumours. TET2 is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced expression in tumours may be an informative biomarker of disease progression and perhaps metastatic disease.

引用

页码：2172 / 2183

页数：12

共 53 条

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Bergeron, Alain ;

Beroukhim, Rameen ;

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Bivol, Adrian ;

Bodenheimer, Tom ;

Boice, Lori ;

Bootwalla, Moiz S. ;

dos Reis, Rodolfo Borges ;

Boutros, Paul C. ;

Bowen, Jay ;

Bowlby, Reanne ;

Boyd, Jeffrey ;

Bradley, Robert K. ;

Breggia, Anne ;

Brimo, Fadi ;

Bristow, Christopher A. ;

Brooks, Denise ;

Broom, Bradley M. ;

Bryce, Alan H. ;

Bubley, Glenn ;

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Blattner, Mirjam ;

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Chakravarty, Debyani ;

Sanborn, J. Zachary ;

Berman, Samuel H. ;

Beroukhim, Rameen ;

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Wu, Chang-Jiun ;

Genovese, Giannicola ;

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Sloan, Andrew ;

Black, Keith L. ;

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Chen, Qiang ;

Chen, Yibin ;

Bian, Chunjing ;

Fujiki, Ryoji ;

Yu, Xiaochun .

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Delhommeau, Francois ;

Dupont, Sabrina ;

Della Valle, Veronique ;

James, Chloe ;

Trannoy, Severine ;

Masse, Aline ;

Kosmider, Olivier ;

Le Couedic, Jean-Pierre ;

Robert, Fabienne ;

Alberdi, Antonio ;

Lecluse, Yann ;

Plo, Isabelle ;

Dreyfus, Francois J. ;

Marzac, Christophe ;

Casadevall, Nicole ;

Lacombe, Catherine ;

Romana, Serge P. ;

Dessen, Philippe ;

Soulier, Jean ;

Viguie, Franck ;

Fontenay, Michaela ;

Vainchenker, William ;

Bernard, Olivier A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (22) :2289-2301

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Dong, Xuesen ;

Sweet, Joan ;

Challis, John R. G. ;

Brown, Theodore ;

Lye, Stephen J. .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (13) :4863-4875

[9] Identification of seven new prostate cancer susceptibility loci through a genome-wide association study [J].

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Kote-Jarai, Zsofia ;

Al Olama, Ali Amin ;

Giles, Graham G. ;

Guy, Michelle ;

Severi, Gianluca ;

Muir, Kenneth ;

Hopper, John L. ;

Henderson, Brian E. ;

Haiman, Christopher A. ;

Schleutker, Johanna ;

Hamdy, Freddie C. ;

Neal, David E. ;

Donovan, Jenny L. ;

Stanford, Janet L. ;

Ostrander, Elaine A. ;

Ingles, Sue A. ;

John, Esther M. ;

Thibodeau, Stephen N. ;

Schaid, Daniel ;

Park, Jong Y. ;

Spurdle, Amanda ;

Clements, Judith ;

Dickinson, Joanne L. ;

Maier, Christiane ;

Vogel, Walther ;

Doerk, Thilo ;

Rebbeck, Timothy R. ;

Cooney, Kathleen A. ;

Cannon-Albright, Lisa ;

Chappuis, Pierre O. ;

Hutter, Pierre ;

Zeegers, Maurice ;

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← 1 2 3 4 5 6 →

共 53 条

[1] The Molecular Taxonomy of Primary Prostate Cancer [J].

Abeshouse, Adam ;

Ahn, Jaeil ;

Akbani, Rehan ;

Ally, Adrian ;

Amin, Samirkumar ;

Andry, Christopher D. ;

Annala, Matti ;

Aprikian, Armen ;

Armenia, Joshua ;

Arora, Arshi ;

Auman, J. Todd ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barbieri, Christopher E. ;

Bauer, Thomas ;

Benz, Christopher C. ;

Bergeron, Alain ;

Beroukhim, Rameen ;

Berrios, Mario ;

Bivol, Adrian ;

Bodenheimer, Tom ;

Boice, Lori ;

Bootwalla, Moiz S. ;

dos Reis, Rodolfo Borges ;

Boutros, Paul C. ;

Bowen, Jay ;

Bowlby, Reanne ;

Boyd, Jeffrey ;

Bradley, Robert K. ;

Breggia, Anne ;

Brimo, Fadi ;

Bristow, Christopher A. ;

Brooks, Denise ;

Broom, Bradley M. ;

Bryce, Alan H. ;

Bubley, Glenn ;

Burks, Eric ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Canes, David ;

Carlotti, Carlos G. ;

Carlsen, Rebecca ;

Carmel, Michel ;

Carroll, Peter R. ;

Carter, Scott L. ;

Cartun, Richard ;

Carver, Brett S. ;

Chan, June M. ;

Chang, Matthew T. ;

Chen, Yu .

CELL, 2015, 163 (04) :1011-1025

[2] Punctuated Evolution of Prostate Cancer Genomes [J].

Baca, Sylvan C. ;

Prandi, Davide ;

Lawrence, Michael S. ;

Mosquera, Juan Miguel ;

Romanel, Alessandro ;

Drier, Yotam ;

Park, Kyung ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Ghandi, Mahmoud ;

Van Allen, Eliezer ;

Kryukov, Gregory V. ;

Sboner, Andrea ;

Theurillat, Jean-Philippe ;

Soong, T. David ;

Nickerson, Elizabeth ;

Auclair, Daniel ;

Tewari, Ashutosh ;

Beltran, Himisha ;

Onofrio, Robert C. ;

Boysen, Gunther ;

Guiducci, Candace ;

Barbieri, Christopher E. ;

Cibulskis, Kristian ;

Sivachenko, Andrey ;

Carter, Scott L. ;

Saksena, Gordon ;

Voet, Douglas ;

Ramos, Alex H. ;

Winckler, Wendy ;

Cipicchio, Michelle ;

Ardlie, Kristin ;

Kantoff, Philip W. ;

Berger, Michael F. ;

Gabriel, Stacey B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Lander, Eric S. ;

Elemento, Olivier ;

Getz, Gad ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Garraway, Levi A. .

CELL, 2013, 153 (03) :666-677

[3] Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer [J].

Barbieri, Christopher E. ;

Baca, Sylvan C. ;

Lawrence, Michael S. ;

Demichelis, Francesca ;

Blattner, Mirjam ;

Theurillat, Jean-Philippe ;

White, Thomas A. ;

Stojanov, Petar ;

Van Allen, Eliezer ;

Stransky, Nicolas ;

Nickerson, Elizabeth ;

Chae, Sung-Suk ;

Boysen, Gunther ;

Auclair, Daniel ;

Onofrio, Robert C. ;

Park, Kyung ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Sheikh, Karen ;

Vuong, Terry ;

Guiducci, Candace ;

Cibulskis, Kristian ;

Sivachenko, Andrey ;

Carter, Scott L. ;

Saksena, Gordon ;

Voet, Douglas ;

Hussain, Wasay M. ;

Ramos, Alex H. ;

Winckler, Wendy ;

Redman, Michelle C. ;

Ardlie, Kristin ;

Tewari, Ashutosh K. ;

Mosquera, Juan Miguel ;

Rupp, Niels ;

Wild, Peter J. ;

Moch, Holger ;

Morrissey, Colm ;

Nelson, Peter S. ;

Kantoff, Philip W. ;

Gabriel, Stacey B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad ;

Rubin, Mark A. ;

Garraway, Levi A. .

NATURE GENETICS, 2012, 44 (06) :685-U107

[4] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[5] The Somatic Genomic Landscape of Glioblastoma [J].

Brennan, Cameron W. ;

Verhaak, Roel G. W. ;

McKenna, Aaron ;

Campos, Benito ;

Noushmehr, Houtan ;

Salama, Sofie R. ;

Zheng, Siyuan ;

Chakravarty, Debyani ;

Sanborn, J. Zachary ;

Berman, Samuel H. ;

Beroukhim, Rameen ;

Bernard, Brady ;

Wu, Chang-Jiun ;

Genovese, Giannicola ;

Shmulevich, Ilya ;

Barnholtz-Sloan, Jill ;

Zou, Lihua ;

Vegesna, Rahulsimham ;

Shukla, Sachet A. ;

Ciriello, Giovanni ;

Yung, W. K. ;

Zhang, Wei ;

Sougnez, Carrie ;

Mikkelsen, Tom ;

Aldape, Kenneth ;

Bigner, Darell D. ;

Van Meir, Erwin G. ;

Prados, Michael ;

Sloan, Andrew ;

Black, Keith L. ;

Eschbacher, Jennifer ;

Finocchiaro, Gaetano ;

Friedman, William ;

Andrews, David W. ;

Guha, Abhijit ;

Iacocca, Mary ;

O'Neill, Brian P. ;

Foltz, Greg ;

Myers, Jerome ;

Weisenberger, Daniel J. ;

Penny, Robert ;

Kucherlapati, Raju ;

Perou, Charles M. ;

Hayes, D. Neil ;

Gibbs, Richard ;

Marra, Marco ;

Mills, Gordon B. ;

Lander, Eric ;

Spellman, Paul ;

Wilson, Richard .

CELL, 2013, 155 (02) :462-477

[6] TET2 promotes histone O-GlcNAcylation during gene transcription [J].

Chen, Qiang ;

Chen, Yibin ;

Bian, Chunjing ;

Fujiki, Ryoji ;

Yu, Xiaochun .

NATURE, 2013, 493 (7433) :561-+

[7] Mutation in TET2 in Myeloid Cancers [J].

Delhommeau, Francois ;

Dupont, Sabrina ;

Della Valle, Veronique ;

James, Chloe ;

Trannoy, Severine ;

Masse, Aline ;

Kosmider, Olivier ;

Le Couedic, Jean-Pierre ;

Robert, Fabienne ;

Alberdi, Antonio ;

Lecluse, Yann ;

Plo, Isabelle ;

Dreyfus, Francois J. ;

Marzac, Christophe ;

Casadevall, Nicole ;

Lacombe, Catherine ;

Romana, Serge P. ;

Dessen, Philippe ;

Soulier, Jean ;

Viguie, Franck ;

Fontenay, Michaela ;

Vainchenker, William ;

Bernard, Olivier A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (22) :2289-2301

[8] Transcriptional activity of androgen receptor is modulated by two RNA splicing factors, PSF and p54nrb [J].

Dong, Xuesen ;

Sweet, Joan ;

Challis, John R. G. ;

Brown, Theodore ;

Lye, Stephen J. .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (13) :4863-4875

[9] Identification of seven new prostate cancer susceptibility loci through a genome-wide association study [J].

Eeles, Rosalind A. ;

Kote-Jarai, Zsofia ;

Al Olama, Ali Amin ;

Giles, Graham G. ;

Guy, Michelle ;

Severi, Gianluca ;

Muir, Kenneth ;

Hopper, John L. ;

Henderson, Brian E. ;

Haiman, Christopher A. ;

Schleutker, Johanna ;

Hamdy, Freddie C. ;

Neal, David E. ;

Donovan, Jenny L. ;

Stanford, Janet L. ;

Ostrander, Elaine A. ;

Ingles, Sue A. ;

John, Esther M. ;

Thibodeau, Stephen N. ;

Schaid, Daniel ;

Park, Jong Y. ;

Spurdle, Amanda ;

Clements, Judith ;

Dickinson, Joanne L. ;

Maier, Christiane ;

Vogel, Walther ;

Doerk, Thilo ;

Rebbeck, Timothy R. ;

Cooney, Kathleen A. ;

Cannon-Albright, Lisa ;

Chappuis, Pierre O. ;

Hutter, Pierre ;

Zeegers, Maurice ;

Kaneva, Radka ;

Zhang, Hong-Wei ;

Lu, Yong-Jie ;

Foulkes, William D. ;

English, Dallas R. ;

Leongamornlert, Daniel A. ;

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