Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer
文献类型：期刊论文
| 作者 | Bernasocchi, Tiziano2,10; El Tekle, Geniver2,10; Bolis, Marco10; Mutti, Azzurra10; Vallerga, Arianna10; Brandt, Laura P.1; Spriano, Filippo2,10; Svinkina, Tanya3; Zoma, Marita2,10; Ceserani, Valentina10 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2021-02-02 |
| 卷号 | 12期号:1页码:18 |
| ISSN号 | 2041-1723 |
| DOI | 10.1038/s41467-020-20820-x |
| 通讯作者 | Theurillat, Jean-Philippe P.(Jean-Philippe.Theurillat@ior.usi.ch) |
| 英文摘要 | Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation. Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition. |
| 资助项目 | Swiss National Science Foundation[PP00P3_150645] ; Swiss National Science Foundation[PP00P3_179072] ; Swiss Cancer League ; Lega Ticinese contro il cancro ; Fidinam Foundation ; National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium[NIH/NCI U24-CA210986] ; National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium[NIH/NCI U01 CA214125] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE RESEARCH |
| WOS记录号 | WOS:000617063000004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/295756]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Theurillat, Jean-Philippe P. |
| 作者单位 | 1.Univ Bern, Dept Biomed Res, CH-3008 Bern, Switzerland 2.Univ Lausanne, CH-1011 Lausanne, VD, Switzerland 3.Broad Inst MIT & Harvard, Cambridge, MA 02142 USA 4.Inst Res Biomed, CH-6500 Bellinzona, TI, Switzerland 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Univ Hosp Zurich, Dept Pathol & Mol Pathol, CH-8091 Zurich, ZH, Switzerland 7.Netherlands Canc Inst, Oncode Inst, NL-1066 CX Amsterdam, Netherlands 8.Inselspital Bern, Dept Urol, Bern, Switzerland 9.Univ Bern, Dept Biomed Res, Urol Res Lab, CH-3010 Bern, Switzerland 10.Univ Svizzera Italiana, Fac Biomed Sci, Inst Oncol Res, CH-6500 Bellinzona, TI, Switzerland |
| 推荐引用方式 GB/T 7714 | Bernasocchi, Tiziano,El Tekle, Geniver,Bolis, Marco,et al. Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer[J]. NATURE COMMUNICATIONS,2021,12(1):18. |
| APA | Bernasocchi, Tiziano.,El Tekle, Geniver.,Bolis, Marco.,Mutti, Azzurra.,Vallerga, Arianna.,...&Theurillat, Jean-Philippe P..(2021).Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer.NATURE COMMUNICATIONS,12(1),18. |
| MLA | Bernasocchi, Tiziano,et al."Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer".NATURE COMMUNICATIONS 12.1(2021):18. |
入库方式： OAI收割
来源：上海药物研究所
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