Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma.
Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma.
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超级增强子抑制剂抑制骨肉瘤中 MYC 驱动的转录扩增和肿瘤进展
DOI：
10.1038/s41413-018-0009-8
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发表时间：
2018
期刊：
影响因子：
12.7
通讯作者：
Jiang YZ
中科院分区：
文献类型：
--
作者：
Chen D;Zhao Z;Huang Z;Chen DC;Zhu XX;Wang YZ;Yan YW;Tang S;Madhavan S;Ni W;Huang ZP;Li W;Ji W;Shen H;Lin S;Jiang YZ
骨肉瘤是最常见的原发骨肉瘤，多发生在年轻人。骨肉瘤的病因是多种多样的，至今仍不完全清楚。为了更好地治疗骨肉瘤患者，迫切需要识别骨肉瘤中新的、重要的致癌因素，并开发更好、更有效的治疗方法。在这项研究中，我们发现癌基因myc在转移性骨肉瘤样本中显著上调。此外，MYC的高表达与骨肉瘤患者的生存不良有关。对骨肉瘤中MYC靶点的分析表明，大多数骨肉瘤超级增强子基因都与MYC结合。用超级增强子抑制剂THZ1和JQ1处理骨肉瘤细胞可以有效地抑制骨肉瘤细胞的增殖、迁移和侵袭。从机制上讲，THZ1处理抑制了一大群含有MYC靶基因的超级增强子，包括CDK6和TGFB2。这些发现表明，MYC驱动的超级增强子信号在骨肉瘤的发生发展中起着至关重要的作用，靶向MYC/超级增强子轴是治疗骨肉瘤的一种有前景的治疗策略。
Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically, THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.
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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：
4.1
作者：
Schedlich, Lynette J.;Yenson, Vanessa M.;Baxter, Robert C.
通讯作者：
Baxter, Robert C.
影响因子：
16.6
作者：
Cayrol F;Praditsuktavorn P;Fernando TM;Kwiatkowski N;Marullo R;Calvo-Vidal MN;Phillip J;Pera B;Yang SN;Takpradit K;Roman L;Gaudiano M;Crescenzo R;Ruan J;Inghirami G;Zhang T;Cremaschi G;Gray NS;Cerchietti L
通讯作者：
Cerchietti L
影响因子：
8.8
作者：
Francavilla C;Lupia M;Tsafou K;Villa A;Kowalczyk K;Rakownikow Jersie-Christensen R;Bertalot G;Confalonieri S;Brunak S;Jensen LJ;Cavallaro U;Olsen JV
通讯作者：
Olsen JV
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS