Pharmacological Inhibition of Core Regulatory Circuitry Liquid-liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma.
Pharmacological Inhibition of Core Regulatory Circuitry Liquid-liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma.
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核心调节回路液-液相分离的药理抑制抑制骨肉瘤的转移和化疗耐药性
DOI：
10.1002/advs.202101895
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Zhao W
中科院分区：
文献类型：
--
作者：
Lu B;Zou C;Yang M;He Y;He J;Zhang C;Chen S;Yu J;Liu KY;Cao Q;Zhao W
液-液相分离(LLP)转录因子在超级增强子(SE)上的组装为哺乳动物细胞中潜在的转录调控提供了一个概念性框架。然而，LLPs在人类恶性肿瘤中由SE的异常调节所驱动的异常转录中的机制仍然是难以理解的。通过结合SE图谱和核心调节电路(CRC)调用算法，勾画出转移性和化疗耐药骨肉瘤的CRC。CRC组分HOXB8和FOSL1在体外产生致密的动态相分离液滴，并在细胞核中产生液状点状。CRC相分离的中断降低了SE区染色质的可及性，并抑制了SE驱动基因启动子的RNA聚合酶II的释放。重要的是，缺乏CRC关键成分会减少骨肉瘤肿瘤的生长和转移。此外，研究还表明，H3K27去甲基酶抑制剂GSK-J4可以特异性地减弱CRC凝聚物。在患者来源的异种移植模型中，药物抑制CRC时相分离导致转移抑制和对化疗药物的重新敏感。综上所述，这项研究揭示了以前未知的CRC因子形成LLP缩合物的机制，并提供了一种基于相分离的药理学策略，针对转移性和化疗耐药的骨肉瘤，靶向不可药物的CRC成分。核心调节回路(CRC)因子在超级增强剂中形成液-液相分离的缩合物，以调节染色质的可及性和致癌转录。在骨肉瘤患者来源的异种移植模型中，GSK-J4抑制CRC时相分离的药理作用可抑制转移和化疗耐药性。
Liquid–liquid phase‐separated (LLPS) transcriptional factor assemblies at super‐enhancers (SEs) provide a conceptual framework for underlying transcriptional control in mammal cells. However, the mechanistic understanding of LLPS in aberrant transcription driven by dysregulation of SEs in human malignancies is still elusive. By integrating SE profiling and core regulatory circuitry (CRC) calling algorithm, the CRC of metastatic and chemo‐resistant osteosarcoma is delineated. CRC components, HOXB8 and FOSL1, produce dense and dynamic phase‐separated droplets in vitro and liquid‐like puncta in cell nuclei. Disruption of CRC phase separation decreases the chromatin accessibility in SE regions and inhibits the release of RNA polymerase II from the promoter of SE‐driven genes. Importantly, absence of CRC key component causes a reduction in osteosarcoma tumor growth and metastasis. Moreover, it is shown that CRC condensates can be specifically attenuated by the H3K27 demethylase inhibitor, GSK‐J4. Pharmacological inhibition of the CRC phase separation results in metastasis suppression and re‐sensitivity to chemotherapy drugs in patient‐derived xenograft model. Taken together, this study reveals a previously unknown mechanism that CRC factors formed LLPS condensates, and provides a phase separation‐based pharmacological strategy to target undruggable CRC components for the treatment of metastatic and chemo‐resistant osteosarcoma. Core regulatory circuitry (CRC) factors forms liquid–liquid phase‐separated condensates at super‐enhancers to regulate chromatin accessibility and oncogenic transcription. Pharmacological inhibition of the CRC phase separation by GSK‐J4 suppresses metastasis and chemoresistance in osteosarcoma patient‐derived xenograft model.
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影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
7
作者：
Saint-André V;Federation AJ;Lin CY;Abraham BJ;Reddy J;Lee TI;Bradner JE;Young RA
通讯作者：
Young RA
YAP的相位分离重新组织了基因组拓扑，以进行长期YAP靶基因表达。
影响因子：
21.3
作者：
Cai D;Feliciano D;Dong P;Flores E;Gruebele M;Porat-Shliom N;Sukenik S;Liu Z;Lippincott-Schwartz J
通讯作者：
Lippincott-Schwartz J
影响因子：
64.8
作者：
Schultz, Matthew D.;He, Yupeng;Whitaker, John W.;Hariharan, Manoj;Mukamel, Eran A.;Leung, Danny;Rajagopal, Nisha;Nery, Joseph R.;Urich, Mark A.;Chen, Huaming;Lin, Shin;Lin, Yiing;Jung, Inkyung;Schmitt, Anthony D.;Selvaraj, Siddarth;Ren, Bing;Sejnowski, Terrence J.;Wang, Wei;Ecker, Joseph R.
通讯作者：
Ecker, Joseph R.
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA