液-液相分离失调 (LLPS) 如何导致女性三阴性乳腺癌 (TNBC) 的肿瘤发生仍不清楚。在这里，我们证明磷酸化组蛋白脱乙酰酶 6（磷酸化 HDAC6）在 TNBC 细胞的细胞核中形成 LLPS 凝聚物，这对于建立异常染色质结构至关重要。 HDAC6 的无序 N 末端结构域和磷酸化残基有助于有效的 LLPS，而核输出区域则发挥负显性效应。通过基于相分离的筛选，我们确定 Nexturastat A 是磷酸-HDAC6 缩合物的特异性破坏剂，可有效抑制肿瘤生长。从机制上讲，importin-β 与磷酸化 HDAC6 相互作用，促进其易位至细胞核，其中 14-3-3θ 介导凝聚物的形成。磷酸化 HDAC6 LLPS 的破坏会重新建立染色质区室和拓扑关联的域边界，从而导致染色质环受到干扰。磷酸化 HDAC6 诱导的异常染色质结构影响 TNBC 中染色质可及性、组蛋白乙酰化、RNA 聚合酶 II 延伸和转录谱。本研究证明磷酸化 HDAC6 LLPS 是 TNBC 染色质结构失调的一种新兴机制。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

How dysregulated liquid-liquid phase separation (LLPS) contributes to the oncogenesis of female triple-negative breast cancer (TNBC) remains unknown. Here we demonstrate that phosphorylated histone deacetylase 6 (phospho-HDAC6) forms LLPS condensates in the nuclei of TNBC cells that are essential for establishing aberrant chromatin architecture. The disordered N-terminal domain and phosphorylated residue of HDAC6 facilitate effective LLPS, whereas nuclear export regions exert a negative dominant effect. Through phase-separation-based screening, we identified Nexturastat A as a specific disruptor of phospho-HDAC6 condensates, which effectively suppresses tumor growth. Mechanistically, importin-β interacts with phospho-HDAC6, promoting its translocation to the nucleus, where 14-3-3θ mediates the condensate formation. Disruption of phospho-HDAC6 LLPS re-established chromatin compartments and topologically associating domain boundaries, leading to disturbed chromatin loops. The phospho-HDAC6-induced aberrant chromatin architecture affects chromatin accessibility, histone acetylation, RNA polymerase II elongation and transcriptional profiles in TNBC. This study demonstrates phospho-HDAC6 LLPS as an emerging mechanism underlying the dysregulation of chromatin architecture in TNBC.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.