MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer.
MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer.
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MYBL2 破坏 Hippo-YAP 通路并赋予前列腺癌去势抵抗和转移潜力
作者：
Li Q;Wang M;Hu Y;Zhao E;Li J;Ren L;Wang M;Xu Y;Liang Q;Zhang D;Lai Y;Liu S;Peng X;Zhu C;Ye L
基本原理：与转移进展相关的雄激素剥夺疗法（ADT）的抗性仍然是前列腺癌（PCa）治疗中具有挑战性的临床任务。目前针对去势抵抗性前列腺癌（CRPC）的靶向疗法并不持久。介导去势治疗耐药导致CRPC进展的确切分子机制仍不清楚。方法：检测MYB原癌基因样2（MYBL 2）在PCa中的表达。通过体外和体内实验确定MYBL 2对ADT反应的影响。使用临床标本（n = 132）和来自癌症基因组图谱（n = 450）的数据分析PCa患者的生存率。通过亚细胞分级分离、免疫印迹、实时荧光定量PCR、染色质免疫沉淀和荧光素酶报告基因检测等方法进一步验证MYBL 2调控基因表达的机制。结果：MYBL 2在CRPC组织和细胞系中表达显著上调。MYBL 2的过表达可通过调节Rho GTP酶RhoA和LATS 1激酶的活性来促进YAP 1的转录活性，从而促进雄激素依赖性PCa细胞的去势抵抗性生长和转移能力。重要的是，靶向MYBL 2，或用雅普/TAZ抑制剂Verteporfin或RhoA抑制剂Simvastatin治疗，逆转了对ADT的抗性并阻断了CRPC细胞的骨转移。最后，高MYBL 2水平与TNM分期、总PSA水平和Gleason评分呈正相关，并预测PCa患者转移复发和预后不良的风险较高。结论：我们的研究结果揭示了一种新的分子机制，赋予耐药性ADT，并提供了一个强有力的理由，对CRPC的潜在治疗策略。
Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.
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DOI：
10.1083/jcb.201009069
发表时间：
2011-05-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Habbig S;Bartram MP;Müller RU;Schwarz R;Andriopoulos N;Chen S;Sägmüller JG;Hoehne M;Burst V;Liebau MC;Reinhardt HC;Benzing T;Schermer B
通讯作者：
Schermer B
影响因子：
8
作者：
Knight, A. S.;Notaridou, M.;Watson, R. J.
通讯作者：
Watson, R. J.
影响因子：
2.3
作者：
Bessa, M;Joaquin, M;Watson, RJ
通讯作者：
Watson, RJ
影响因子：
3.8
作者：
Hoque, Ashraful;Chen, Hongli;Xu, Xiao-Chun
通讯作者：
Xu, Xiao-Chun
影响因子：
50.3
作者：
Li, Zhiqiang;Razavi, Pedram;Chandarlapaty, Sarat
通讯作者：
Chandarlapaty, Sarat