Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, 6500, Bellinzona, TI, Switzerland.
University of Lausanne, 1011, Lausanne, VD, Switzerland.
Nat Commun. 2021 Feb 2;12(1):734. doi: 10.1038/s41467-020-20820-x.
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.
在肿瘤基因组中具有相互排斥突变模式的驱动基因被认为在肿瘤发生中具有重叠作用。相比之下，我们在这里表明，涉及 ERG 转录因子和泛素连接酶接头 SPOP 的相互排斥的前列腺癌驱动改变是合成性的。在分子水平上，不相容的癌症途径由 SPOP 的相反功能驱动。ERG 上调野生型 SPOP 以抑制雄激素受体 (AR) 信号，并通过降解溴结构域组蛋白阅读器 ZMYND11 来维持 ERG 活性。相反，SPOP 突变型肿瘤稳定 ZMYND11 以抑制 ERG 功能并启用致癌雄激素受体信号。这种二分法调节了 AR 通路中治疗干预的反应。虽然突变型 SPOP 使肿瘤细胞易受雄激素剥夺疗法的影响，但 ERG 促进了对高剂量雄激素治疗和野生型 SPOP 的药理学抑制的敏感性。更一般地，这些结果定义了一类独特的拮抗癌症驱动因素，并为其治疗利用制定了蓝图。
