It remains unknown if biophysical or material properties of biomolecular condensates regulate cancer. Here we show that AKAP95, a nuclear protein that regulates transcription and RNA splicing, plays an important role in tumorigenesis by supporting cancer cell growth and suppressing oncogene-induced senescence. AKAP95 forms phase-separated and liquid-like condensates in vitro and in nucleus. Mutations of key residues to different amino acids perturb AKAP95 condensation in opposite directions. Importantly, the activity of AKAP95 in splice regulation is abolished by disruption of condensation, significantly impaired by hardening of condensates, and regained by substituting its condensation-mediating region with other condensation-mediating regions from irrelevant proteins. Moreover, the abilities of AKAP95 in regulating gene expression and supporting tumorigenesis require AKAP95 to form condensates with proper liquidity and dynamicity. These results link phase separation to tumorigenesis and uncover an important role of appropriate biophysical properties of protein condensates in gene regulation and cancer.

目前尚不清楚生物分子凝聚物的生物物理或材料特性是否调节癌症。在这里，我们发现 AKAP95 是一种调节转录和 RNA 剪接的核蛋白，通过支持癌细胞生长和抑制癌基因诱导的衰老，在肿瘤发生中发挥重要作用。 AKAP95 在体外和细胞核中形成相分离的液体状冷凝物。不同氨基酸的关键残基突变会以相反方向扰乱 AKAP95 缩合。重要的是，AKAP95 在剪接调节中的活性因缩合破坏而被消除，因缩合体硬化而显着受损，并通过用来自不相关蛋白质的其他缩合介导区域取代其缩合介导区域而恢复。此外，AKAP95调节基因表达和支持肿瘤发生的能力要求AKAP95形成具有适当流动性和动态性的冷凝物。这些结果将相分离与肿瘤发生联系起来，并揭示了蛋白质缩合物的适当生物物理特性在基因调控和癌症中的重要作用。