Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer

doi:10.1038/s41467-020-20820-x

	Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer
	Bernasocchi, Tiziano 2,3; El Tekle, Geniver 2,3; Bolis, Marco 2; Mutti, Azzurra 2; Vallerga, Arianna 2; Brandt, Laura P.4; Spriano, Filippo 2,3; Svinkina, Tanya 5; Zoma, Marita 2,3; Ceserani, Valentina 2
刊名	NATURE COMMUNICATIONS
	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
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295756]
专题	中国科学院上海药物研究所
通讯作者	Theurillat, Jean-Philippe P.
作者单位	1.Inst Res Biomed, CH-6500 Bellinzona, TI, Switzerland 2.Univ Svizzera Italiana, Fac Biomed Sci, Inst Oncol Res, CH-6500 Bellinzona, TI, Switzerland 3.Univ Lausanne, CH-1011 Lausanne, VD, Switzerland 4.Univ Bern, Dept Biomed Res, CH-3008 Bern, Switzerland 5.Broad Inst MIT & Harvard, Cambridge, MA 02142 USA 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Univ Hosp Zurich, Dept Pathol & Mol Pathol, CH-8091 Zurich, ZH, Switzerland 8.Netherlands Canc Inst, Oncode Inst, NL-1066 CX Amsterdam, Netherlands 9.Univ Bern, Dept Biomed Res, Urol Res Lab, CH-3010 Bern, Switzerland 10.Inselspital Bern, Dept Urol, Bern, 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.