Hyper-acetylation contributes to the sensitivity of chemo-resistant prostate cancer cells to histone deacetylase inhibitor Trichostatin A.
Hyper-acetylation contributes to the sensitivity of chemo-resistant prostate cancer cells to histone deacetylase inhibitor Trichostatin A.
复制标题
过度乙酰化有助于化疗耐药性前列腺癌细胞对组蛋白脱乙酰酶抑制剂曲古抑菌素 A 的敏感性
DOI：
10.1111/jcmm.13475
复制
发表时间：
2018-03
影响因子：
5.3
通讯作者：
Yuan H
中科院分区：
文献类型：
--
作者：
Xu Q;Liu X;Zhu S;Hu X;Niu H;Zhang X;Zhu D;Nesa EU;Tian K;Yuan H
迫切需要治疗药物来治疗对雄激素剥夺和化疗无反应的转移性去势难治性前列腺癌（mCRPC）。我们的筛选试验表明，化疗耐药前列腺癌（PCa）细胞比成对的敏感PCa细胞对HDAC抑制剂更敏感，如体外和体内细胞增殖和凋亡所示。动力学研究表明，TSA诱导的细胞凋亡明显依赖于早期转录和蛋白质合成的增强，随后引起ER应激和细胞凋亡。ChIP分析表明TSA增加了H4 K16的乙酰化，促进了ER应激基因的转录。还在TSA给药动物中验证了Ac-H4 K16、ATF 3和ATF 4的变化。进一步的研究表明，HDACs的酶活性更高，抗性细胞中乙酰化蛋白的增加。耐药细胞中较高的核质乙酰辅酶A是蛋白质乙酰化状态升高和生长状态更旺盛的原因。这些结果强烈支持HDAC抑制剂用于治疗化疗耐药mCRPC的临床前应用。
Therapeutic agents are urgently needed for treating metastatic castration‐refractory prostate cancer (mCRPC) that is unresponsive to androgen deprivation and chemotherapy. Our screening assays demonstrated that chemotherapy‐resistant prostate cancer (PCa) cells are more sensitive to HDAC inhibitors than paired sensitive PCa cells, as demonstrated by cell proliferation and apoptosis in vitro and in vivo. Kinetic study revealed that TSA‐induced apoptosis was significantly dependent on enhanced transcription and protein synthesis in an early stage, which subsequently caused ER stress and apoptosis. ChIP analysis indicated that TSA increased H4K16 acetylation, promoting ER stress gene transcription. The changes in Ac‐H4K16, ATF3 and ATF4 were also validated in TSA‐treated animals. Further study revealed the higher enzyme activity of HDACs and an increase in acetylated proteins in resistant cells. The higher nucleocytoplasmic acetyl‐CoA in resistant cells was responsible for elevated acetylation status of protein and a more vigorous growth state. These results strongly support the pre‐clinical application of HDAC inhibitors for treating chemotherapy‐resistant mCRPC.
登录
查看更多内容
影响因子：
3.7
作者：
Sakamoto T;Kobayashi S;Yamada D;Nagano H;Tomokuni A;Tomimaru Y;Noda T;Gotoh K;Asaoka T;Wada H;Kawamoto K;Marubashi S;Eguchi H;Doki Y;Mori M
通讯作者：
Mori M
影响因子：
8
作者：
Makarovskiy, AN;Siryaporn, E;Akerley, W
通讯作者：
Akerley, W
影响因子：
12.4
作者：
Peixoto, P.;Castronovo, V.;Mottet, D.
通讯作者：
Mottet, D.
影响因子：
3.9
作者：
Prasad, Preethi;Vasquez, Hernan;Wolff, Johannes E. A.
通讯作者：
Wolff, Johannes E. A.
影响因子：
6.4
作者：
Castro-Galache, MD;Ferragut, JA;Saceda, M
通讯作者：
Saceda, M