ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
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DOI：
10.1016/j.ccell.2017.05.003
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发表时间：
2017-06-12
期刊：
影响因子：
50.3
通讯作者：
Mahajan NP
中科院分区：
文献类型：
--
作者：
Mahajan K;Malla P;Lawrence HR;Chen Z;Kumar-Sinha C;Malik R;Shukla S;Kim J;Coppola D;Lawrence NJ;Mahajan NP
雄激素受体（AR）是前列腺癌进展到去势抵抗（CRPC）状态的关键。AR拮抗剂由于不能抑制AR或其剪接变体AR-V7的表达而无效。在这里，我们报告，酪氨酸激酶ACK 1（TNK 2）磷酸化组蛋白H4在酪氨酸88上游的AR转录起始位点。WDR 5/MLL 2复合物读取H4-Y88-磷酸化标记，并沉积转录激活H3 K4-三甲基标记，促进AR转录。通过ACK 1抑制剂（R）-9bMS对pY 88-H4表观遗传标记的恢复使初始和恩杂鲁胺耐药前列腺癌细胞敏化，并降低AR和AR-V7水平以减轻CRPC肿瘤生长。因此，前馈ACK 1/pY 88-H4/WDR 5/MLL 2/AR表观遗传电路驱动CRPC，并且对于维持恶性状态是必需的。Mahajan等人报道，ACK 1磷酸化AR转录起始位点上游Y88处的组蛋白H4，导致WDR 5/MLL 2复合物介导的AR转录增加。ACK 1的抑制逆转pY 88-H4标记并降低AR和AR-V7水平以减轻去势抵抗性前列腺肿瘤生长。
Androgen receptor (AR) is critical for the progression of prostate cancer to castration resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feed-forward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state. Mahajan et al. report that ACK1 phosphorylates histone H4 at Y88 upstream of the AR transcription start site, leading to the WDR5/MLL2 complex-mediated increase of AR transcription. Inhibition of ACK1 reverses the pY88-H4 marks and reduces AR and AR-V7 levels to mitigate castration resistant prostate tumor growth.
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影响因子：
4.8
作者：
Mahajan, Kiran;Lawrence, Harshani R.;Mahajan, Nupam P.
通讯作者：
Mahajan, Nupam P.
雄激素受体信号调节前列腺癌的 DNA 修复。
影响因子：
28.2
作者：
Polkinghorn WR;Parker JS;Lee MX;Kass EM;Spratt DE;Iaquinta PJ;Arora VK;Yen WF;Cai L;Zheng D;Carver BS;Chen Y;Watson PA;Shah NP;Fujisawa S;Goglia AG;Gopalan A;Hieronymus H;Wongvipat J;Scardino PT;Zelefsky MJ;Jasin M;Chaudhuri J;Powell SN;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
16.8
作者：
Mahajan K;Fang B;Koomen JM;Mahajan NP
通讯作者：
Mahajan NP
DOI：
10.1073/pnas.0700420104
发表时间：
2007-05-15
影响因子：
11.1
作者：
Mahajan, Nupam P.;Liu, Yuanbo;Whang, Young E.
通讯作者：
Whang, Young E.