The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling
The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling
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BET Bromodomain 抑制剂 JQ1 通过调节 YAP/p21/c-Myc 信号传导抑制软骨肉瘤细胞生长
DOI：
10.1002/jcb.25863
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发表时间：
2017
影响因子：
4
通讯作者：
Zha Zhen Gang
中科院分区：
文献类型：
--
作者：
Zhang Huan Tian;Gui Tao;Sang Yuan;Yang Jie;Li Yu Hang;Liang Gui Hong;Li Thomas;He Qing Yu;Zha Zhen Gang
软骨肉瘤是第二常见的原发性骨恶性肿瘤，通常对常规化疗和放疗更耐药。因此，开发有效的辅助治疗是必要的。最近，靶向表观遗传调节因子如溴结构域和末端外结构域（BET）蛋白已取得巨大成功。例如，布罗莫结构域抑制剂JQ 1已显示在体外和体内抑制几种癌细胞的生长。在此，我们证明JQ 1显著抑制软骨肉瘤细胞生长和集落形成。JQ 1还诱导明显的G1期细胞周期停滞，与p21 WAF 1/CIP 1、p27 Kip 1和Cyclin D1表达的上调以及Cyclin E2表达的下调一致。JQ 1可诱导SW 1353细胞的早衰，延长JQ 1的作用时间可引起细胞凋亡。从机制上讲，JQ 1诱导的细胞生长抑制与c-Myc和Bcl-xL的抑制相关，这是细胞周期控制和抗凋亡的主要基因。此外，我们证明了在JQ 1处理后，p21负调控c-Myc和Bcl-xL的表达，并且SW 1353和Hs 819.T细胞的生长抑制和p21的诱导主要由LATS 1/雅普信号传导调节，而不是通过p53依赖性方式。综上所述，我们揭示了JQ 1通过调控雅普/p21/c-Myc/Bcl-xL信号轴抑制软骨肉瘤细胞增殖、诱导细胞衰老和凋亡的新机制。J.细胞。118：2182-2192，2017.© 2017 Wiley Periodicals，Inc.
Chondrosarcoma, the second‐most frequent primary bone malignancy, is generally more resistant to conventional chemotherapy and radiotherapy. Therefore, the development of an effective adjuvant therapy is necessary. Recently, targeting the epigenetic regulator such as bromodomain and extraterminal domain (BET) proteins has achieved great success. For instance, the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo. Herein, we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation. JQ1 also induced marked G1‐phase cell cycle arrest coincided with the up‐regulation of p21WAF1/CIP1, p27Kip1, and Cyclin D1 expression, and the down‐regulation of Cyclin E2 expression. Moreover, JQ1 induced the premature senescence of SW 1353 cells, and that prolong treatment of JQ1 caused cell apoptosis. Mechanistically, the JQ1‐induced cell growth inhibition was correlated with the suppression of c‐Myc and Bcl‐xL, which are the prime genes for cell cycle control and anti‐apoptosis. Furthermore, we demonstrated that p21 negatively regulated the expression of c‐Myc and Bcl‐xL upon JQ1 treatment, and that the growth inhibition of SW 1353 and Hs 819.T cells and induction of p21 were predominantly regulated by the LATS1/YAP signaling but not through a p53‐dependent manner. In conclusion, we disclosed a novel mechanism that JQ1 inhibits cell proliferation, induces cell senescence and apoptosis of chondrosarcoma cells through the regulation of the YAP/p21/c‐Myc/Bcl‐xL signaling axis. J. Cell. Biochem. 118: 2182–2192, 2017. © 2017 Wiley Periodicals, Inc.