Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation

被引：136

作者：

An, Jian ^{[1
,2
,3
]}

Ren, Shancheng ^{[4
]}

Murphy, Stephen J. ^{[5
]}

Dalangood, Sumiya ^{[6
]}

Chang, Cunjie ^{[6
]}

Pang, Xiaodong ^{[7
]}

Cui, Yangyan ^{[6
]}

Wang, Liguo ^{[8
]}

Pan, Yunqian ^{[1
]}

Zhang, Xiaowei ^{[1
]}

Zhu, Yasheng ^{[4
]}

Wang, Chenji ^{[9
]}

Halling, Geoffrey C. ^{[5
]}

Cheng, Liang ^{[10
]}

Sukov, William R. ^{[11
]}

Karnes, R. Jeffrey ^{[2
,5
]}

Vasmatzis, George ^{[5
,12
]}

Zhang, Qing ^{[6
]}

Zhang, Jun ^{[11
]}

Cheville, John C. ^{[5
,11
]}

Yan, Jun ^{[6
]}

Sun, Yinghao ^{[4
]}

Huang, Haojie ^{[1
,2
,3
]}

机构：

[1] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA

[2] Mayo Clin, Coll Med, Dept Urol, Rochester, MN 55905 USA

[3] Mayo Clin, Coll Med, Ctr Canc, Rochester, MN 55905 USA

[4] Second Mil Med Univ, Shanghai Changhai Hosp, Dept Urol, Shanghai 200433, Peoples R China

[5] Mayo Clin, Coll Med, Ctr Individualized Med, Rochester, MN 55905 USA

[6] Nanjing Univ, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China

[7] Fudan Univ, Dept Phys, State Key Lab Surface Phys, Shanghai 200433, Peoples R China

[8] Mayo Clin, Coll Med, Dept Med Informat & Stat, Rochester, MN 55905 USA

[9] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China

[10] Indiana Univ Sch Med, Dept Pathol, Indianapolis, IN 46202 USA

[11] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[12] Mayo Clin, Coll Med, Dept Mol Med, Rochester, MN 55905 USA

来源：

MOLECULAR CELL | 2015年 / 59卷 / 06期

基金：

美国国家卫生研究院; 国家教育部博士点专项基金资助; 中国国家自然科学基金;

关键词：

PROSTATE-CANCER; GENE FUSIONS; ANDROGEN RECEPTOR; TRANSCRIPTION FACTOR; UBIQUITIN LIGASES; KIDNEY CANCER; MUTATIONS; PTEN; PHOSPHORYLATION; TUMORIGENESIS;

D O I：

10.1016/j.molcel.2015.07.025

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：

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

引用

页码：904 / 916

页数：13

共 43 条

[1] Destruction of Full-Length Androgen Receptor by Wild-Type SPOP, but Not Prostate-Cancer-Associated Mutants [J].

An, Jian ;

Wang, Chenji ;

Deng, Yibin ;

Yu, Long ;

Huang, Haojie .

CELL REPORTS, 2014, 6 (04) :657-669

[2] ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients [J].

Baena, Esther ;

Shao, Zhen ;

Linn, Douglas E. ;

Glass, Kimberly ;

Hamblen, Melanie J. ;

Fujiwara, Yuko ;

Kim, Jonghwan ;

Minh Nguyen ;

Zhang, Xin ;

Godinho, Frank J. ;

Bronson, Roderick T. ;

Mucci, Lorelei A. ;

Loda, Massimo ;

Yuan, Guo-Cheng ;

Orkin, Stuart H. ;

Li, Zhe .

GENES & DEVELOPMENT, 2013, 27 (06) :683-698

[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 genomic complexity of primary human prostate cancer [J].

Berger, Michael F. ;

Lawrence, Michael S. ;

Demichelis, Francesca ;

Drier, Yotam ;

Cibulskis, Kristian ;

Sivachenko, Andrey Y. ;

Sboner, Andrea ;

Esgueva, Raquel ;

Pflueger, Dorothee ;

Sougnez, Carrie ;

Onofrio, Robert ;

Carter, Scott L. ;

Park, Kyung ;

Habegger, Lukas ;

Ambrogio, Lauren ;

Fennell, Timothy ;

Parkin, Melissa ;

Saksena, Gordon ;

Voet, Douglas ;

Ramos, Alex H. ;

Pugh, Trevor J. ;

Wilkinson, Jane ;

Fisher, Sheila ;

Winckler, Wendy ;

Mahan, Scott ;

Ardlie, Kristin ;

Baldwin, Jennifer ;

Simons, Jonathan W. ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Kantoff, Philip W. ;

Chin, Lynda ;

Gabriel, Stacey B. ;

Gerstein, Mark B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Tewari, Ashutosh ;

Lander, Eric S. ;

Getz, Gad ;

Rubin, Mark A. ;

Garraway, Levi A. .

NATURE, 2011, 470 (7333) :214-220

[5] SPOP Mutations in Prostate Cancer across Demographically Diverse Patient Cohorts [J].

Blattner, Mirjam ;

Lee, Daniel J. ;

O'Reilly, Catherine ;

Park, Kyung ;

MacDonald, Theresa Y. ;

Khani, Francesca ;

Turner, Kevin R. ;

Chiu, Ya-Lin ;

Wild, Peter J. ;

Dolgalev, Igor ;

Heguy, Adriana ;

Sboner, Andrea ;

Ramazangolu, Sinan ;

Hieronymus, Haley ;

Sawyers, Charles ;

Tewari, Ashutosh K. ;

Moch, Holger ;

Yoon, Ghil Suk ;

Known, Yong Chul ;

Andren, Ove ;

Fall, Katja ;

Demichelis, Francecsa ;

Mosquera, Juan Miguel ;

Robinson, Brian D. ;

Barbieri, Christopher E. ;

Rubin, Mark A. .

NEOPLASIA, 2014, 16 (01) :14-U34

[6] Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate [J].

Carver, Brett S. ;

Tran, Jennifer ;

Gopalan, Anuradha ;

Chen, Zhenbang ;

Shaikh, Safa ;

Carracedo, Arkaitz ;

Alimonti, Andrea ;

Nardella, Caterina ;

Varmeh, Shohreh ;

Scardino, Peter T. ;

Cordon-Cardo, Carlos ;

Gerald, William ;

Pandolfi, Pier Paolo .

NATURE GENETICS, 2009, 41 (05) :619-624

[7] Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2 [J].

Chen, Shuai ;

Bohrer, Laura R. ;

Rai, Aswathy N. ;

Pan, Yunqian ;

Gan, Lu ;

Zhou, Xianzheng ;

Bagchi, Anindya ;

Simon, Jeffrey A. ;

Huang, Haojie .

NATURE CELL BIOLOGY, 2010, 12 (11) :1108-U118

[8] ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss [J].

Chen, Yu ;

Chi, Ping ;

Rockowitz, Shira ;

Iaquinta, Phillip J. ;

Shamu, Tambudzai ;

Shukla, Shipra ;

Gao, Dong ;

Sirota, Inna ;

Carver, Brett S. ;

Wongvipat, John ;

Scher, Howard I. ;

Zheng, Deyou ;

Sawyers, Charles L. .

NATURE MEDICINE, 2013, 19 (08) :1023-+

[9] Role of the TMPRSS2-ERG gene fusion in prostate cancer [J].

Chinnaiyan, Arul M. .

NEOPLASIA, 2008, 10 (02) :177-U23

[10] Diversity of TMPRSS2-ERG fusion transcripts in the human prostate [J].

Clark, J. ;

Merson, S. ;

Jhavar, S. ;

Flohr, P. ;

Edwards, S. ;

Foster, C. S. ;

Eeles, R. ;

Martin, F. L. ;

Phillips, D. H. ;

Crundwell, M. ;

Christmas, T. ;

Thompson, A. ;

Fisher, C. ;

Kovacs, G. ;

Cooper, C. S. .

ONCOGENE, 2007, 26 (18) :2667-2673

← 1 2 3 4 5 →