Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
Nat Cell Biol. 2023 Feb;25(2):323-336. doi: 10.1038/s41556-022-01069-6. Epub 2023 Feb 2.
Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.
核内 HIPPO-YAP 融合蛋白的定位与幕上室管膜瘤的发生有关。在这里，我们出乎意料地发现，在源自神经祖细胞的室管膜瘤发生中，反复出现的患者源性 YAP 融合蛋白，即 YAP-MAMLD1 和 C11ORF95-YAP 的液-液相分离，而非核内定位，是基础。突变和嵌合体分析表明，一个固有无序区域促进了 YAP 融合蛋白的寡聚化，形成核点状、无膜的凝聚物。YAP 融合与转录激活因子 GCN4 的卷曲螺旋结构域的融合也诱导核内凝聚物的形成，从而促进室管膜瘤的形成。YAP-MAMLD1 将转录因子和共激活因子（包括 BRD4、MED1 和 TEAD）浓缩在凝聚物中，同时排除转录抑制性 PRC2，并诱导长程增强子-启动子相互作用，促进转录和致癌程序。阻断凝聚物介导的转录共激活因子活性可抑制肿瘤发生，表明液-液相分离对 YAP 融合蛋白在室管膜瘤中的致癌活性具有关键作用。含有无规卷曲区域特征的 YAP 融合蛋白在人类肿瘤中很常见，这表明核内凝聚物可能成为治疗 YAP 融合蛋白诱导的癌症的靶点。
