Chromatin-regulating proteins as targets for cancer therapy.
Chromatin-regulating proteins as targets for cancer therapy.
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DOI：
10.1093/jrr/rrt227
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发表时间：
2014-07
影响因子：
2
通讯作者：
Kohno T
中科院分区：
文献类型：
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作者：
Oike T;Ogiwara H;Amornwichet N;Nakano T;Kohno T
染色质调节蛋白代表了癌症治疗的一大类新靶点。在放射治疗的背景下，组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）对组蛋白的乙酰化和脱乙酰化在电离辐射产生的DNA双链断裂的修复中起重要作用，因此是放射增敏的有吸引力的靶点。HAT的小分子抑制剂（garcinol，漆树酸和姜黄素）和HDAC（伏立诺他，丁酸钠和丙戊酸）已被证明在临床前模型中使癌细胞对电离辐射敏感，其中一些分子正在临床试验中进行测试，无论是单独使用还是与放疗联合使用。与此同时，最近的大规模基因组分析已经确定了在各种人类癌症中编码染色质调节蛋白的基因中的频繁突变，特别是在编码SWI/SNF染色质重塑复合物的亚基的基因中。这些观察结果促使研究人员开发针对携带这些突变的癌症的靶向疗法。MLL重排白血病中的DOT 1 L抑制、EZH 2突变或MLL重排恶性血液病和SNF 5缺陷型肿瘤中的EZH 2抑制、各种恶性血液病中的BRD 4抑制以及BRG 1缺陷型肿瘤中的BRM抑制已在临床前模型中显示出有希望的抗肿瘤作用，这些策略目前正等待临床应用。总的来说，到目前为止收集的数据表明，靶向染色质调节蛋白是未来癌症治疗的一个有前途的策略，包括放射治疗和分子靶向化疗。
Chromatin-regulating proteins represent a large class of novel targets for cancer therapy. In the context of radiotherapy, acetylation and deacetylation of histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the repair of DNA double-strand breaks generated by ionizing irradiation, and are therefore attractive targets for radiosensitization. Small-molecule inhibitors of HATs (garcinol, anacardic acid and curcumin) and HDACs (vorinostat, sodium butyrate and valproic acid) have been shown to sensitize cancer cells to ionizing irradiation in preclinical models, and some of these molecules are being tested in clinical trials, either alone or in combination with radiotherapy. Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers. These observations have driven researchers toward development of targeted therapies against cancers carrying these mutations. DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application. Overall, the data collected so far suggest that targeting chromatin-regulating proteins is a promising strategy for tomorrow's cancer therapy, including radiotherapy and molecularly targeted chemotherapy.
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影响因子：
120.1
作者：
Chan, Denise A.;Giaccia, Amato J.
通讯作者：
Giaccia, Amato J.
影响因子：
3.4
作者：
Chen, Xufeng;Wong, Patty;Wong, Jeffrey Y. C.
通讯作者：
Wong, Jeffrey Y. C.
DOI：
10.1016/j.ijrobp.2010.03.010
发表时间：
2010-09-01
影响因子：
7
作者：
Blattmann, Claudia;Oertel, Susanne;Weber, Klaus-J.
通讯作者：
Weber, Klaus-J.
影响因子：
4.8
作者：
Balasubramanyam, K;Varier, RA;Kundu, TK
通讯作者：
Kundu, TK
影响因子：
64.8
作者：
通讯作者：
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