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磷酸- hdac6相分离驱动三阴性乳腺癌异常染色质结构

原文发布日期：2024-08-28

英文摘要：

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.

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磷酸- hdac6相分离驱动三阴性乳腺癌异常染色质结构

Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer

原文发布日期：2024-08-28

英文摘要：

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.

摘要翻译：

尚不清楚雌性三阴性乳腺癌（TNBC）中液态-液态相分化的异常（dysregulated liquid–liquid phase separation, LLPS）是如何促进癌症发生的。本研究展示了磷酸化过的组蛋白去甲基酶6（phosphorylated histone deacetylase 6，pHDAc6）在TNBC细胞核中形成的关键液态-液态相分化凝集体，这些凝集体对于建立异常染色质构象至关重要。蛋白质N端的无序区域和pHDAc6的磷酸化残基促进了有效的液态-液态相分化过程，然而核孔区域对pHDAc6液态-液态相分化的效果是负面的。通过基于液态-液态相分化的筛选，我们鉴定出了Nexturastat A作为pHDAc6凝集体的具体破坏者，能够有效抑制肿瘤生长。机制上讲，importin-β与磷酸化过的组蛋白去甲基酶6相互作用，促进其转运至核内，其中14-3-3θ介导了凝集体的形成。pHDAc6液态-液态相分化的破坏使染色质区域和拓扑学关联域边界重新建立，导致染色质环路结构紊乱。磷酸化过的组蛋白去甲基酶6诱导的异常染色质构象对TNBC中的染色质可及性、 histone acetylation、 RNA聚合体 elongation以及转录调控图谱造成了影响。本研究展示了pHDAc6液态-液态相分化的异常作为TNBC中染色质构象紊乱的新兴调控机制。