Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer.
Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer.
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DOI：
10.1038/s41467-020-20820-x
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发表时间：
2021-02-02
影响因子：
16.6
通讯作者：
Theurillat JP
中科院分区：
文献类型：
--
作者：
Bernasocchi T;El Tekle G;Bolis M;Mutti A;Vallerga A;Brandt LP;Spriano F;Svinkina T;Zoma M;Ceserani V;Rinaldi A;Janouskova H;Bossi D;Cavalli M;Mosole S;Geiger R;Dong Z;Yang CG;Albino D;Rinaldi A;Schraml P;Linder S;Carbone GM;Alimonti A;Bertoni F;Moch H;Carr SA;Zwart W;Kruithof-de Julio M;Rubin MA;Udeshi ND;Theurillat JP
在肿瘤基因组中具有互斥突变模式的驱动基因被认为在肿瘤发生中具有重叠的作用。相反，我们在这里表明，涉及ERG转录因子和泛素连接酶适配器SPOP的相互排斥的前列腺癌驱动因素改变是合成病症。在分子水平上，不相容的癌症途径由SPOP中相反的功能驱动。ERG通过降解溴结构域组蛋白阅读器ZMYND11上调野生型SPOP以抑制雄激素受体(AR)信号并维持ERG活性。相反，SPOP突变的肿瘤稳定ZMYND11以抑制ERG功能并启动致癌雄激素受体信号转导。这种二分法调节AR通路中对治疗干预的反应。突变的SPOP使肿瘤细胞对雄激素剥夺治疗敏感，而ERG促进了对高剂量雄激素治疗的敏感性和野生型SPOP的药理抑制。更广泛地说，这些结果定义了一类不同的拮抗癌症驱动因素，并为他们的治疗开发制定了蓝图。涉及ERG转录因子的基因融合和泛素连接酶适配器SPOP的点突变是前列腺癌中相互排他性存在的两个主干突变。在这里，作者表明SPOP的突变使前列腺癌细胞对抗雄激素治疗敏感，ERG的存在促进了对高剂量雄激素和SPOP抑制的敏感性。
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.
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影响因子：
30.8
作者：
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
通讯作者：
Pandolfi, Pier Paolo
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H