Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
Nat Cancer. 2024 Nov;5(11):1622-1640. doi: 10.1038/s43018-024-00816-y. Epub 2024 Aug 28.
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.
磷酸化组蛋白去乙酰化酶 6（phospho-HDAC6）如何失调液-液相分离（LLPS）导致女性三阴性乳腺癌（TNBC）的发生尚不清楚。在这里，我们证明磷酸化组蛋白去乙酰化酶 6（phospho-HDAC6）在 TNBC 细胞的核中形成 LLPS 凝聚物，这对于建立异常染色质结构是必不可少的。HDAC6 的无序 N 端结构域和磷酸化残基有助于有效的 LLPS，而核输出区域则产生负显性效应。通过基于相分离的筛选，我们鉴定出 Nexturastat A 是磷酸化 HDAC6 凝聚物的特异性破坏剂，可有效抑制肿瘤生长。在机制上，importin-β 与 phospho-HDAC6 相互作用，促进其易位到核内，在核内，14-3-3θ 介导凝聚物的形成。破坏 phospho-HDAC6 的 LLPS 可重建染色质隔室和拓扑关联结构域边界，导致染色质环紊乱。phospho-HDAC6 诱导的异常染色质结构会影响 TNBC 中的染色质可及性、组蛋白乙酰化、RNA 聚合酶 II 延伸和转录谱。本研究表明，phospho-HDAC6 的 LLPS 是 TNBC 中染色质结构失调的一种新机制。
