Chromatin Regulation by HP1γ Contributes to Survival of 5-Azacytidine-Resistant Cells.
Chromatin Regulation by HP1γ Contributes to Survival of 5-Azacytidine-Resistant Cells.
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DOI：
10.3389/fphar.2018.01166
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发表时间：
2018
影响因子：
5.6
通讯作者：
Ohyashiki JH
中科院分区：
文献类型：
--
作者：
Imanishi S;Umezu T;Kobayashi C;Ohta T;Ohyashiki K;Ohyashiki JH
最近对血液肿瘤治疗的研究主要集中在靶向表观遗传调节因子上。DNA甲基转移酶抑制剂5-氮杂胞苷(5-azacytidine，AZA)在治疗骨髓增生异常综合征患者中取得了良好的效果。其药理活性的机制涉及许多细胞过程，包括组蛋白修饰，但对AZA耐药细胞的染色质调节在很大程度上仍不清楚。因此，我们比较了氮杂氮耐药的人白血病细胞和对氮杂氮敏感的白血病细胞组蛋白修饰的反应以及它们的读者对氮杂氮治疗的反应，以确定氮杂氮耐药的血液肿瘤中的新的分子靶点(S)。我们观察到组蛋白H3特异性阅读器蛋白的甲基化赖氨酸γ在治疗后在对氮杂环己酮敏感的细胞中减少，而在氮杂环己酮耐药的细胞中不影响hp1家族蛋白。针对hP1shRNA的表达降低了耐药细胞的存活率，诱导了细胞的凋亡，同时伴随着γ/BRCA1信号的下调，提示γ对染色质的调节在耐药细胞的存活中起着关键作用。此外，溴域抑制剂I-BET151对氮杂氮敏感和耐药细胞Hp1γ蛋白的抑制作用比对氮杂氮敏感的细胞更强。我们的发现表明，影响表观遗传阅读器蛋白并以hp1γ为靶点的aza或溴域抑制剂是一种新的治疗策略，可用于治疗具有aza耐药的血液肿瘤患者。
Recent investigations of the treatment for hematologic neoplasms have focused on targeting epigenetic regulators. The DNA methyltransferase inhibitor 5-azacytidine (AZA) has produced good results in the treatment of patients with myelodysplastic syndromes. The mechanism underlying its pharmacological activity involves many cellular processes including histone modifications, but chromatin regulation in AZA-resistant cells is still largely unknown. Therefore, we compared human leukemia cells with AZA resistance and their AZA-sensitive counterparts with regard to the response of histone modifications and their readers to AZA treatment to identify novel molecular target(s) in hematologic neoplasms with AZA resistance. We observed an a decrease of HP1γ, a methylated lysine 9 of histone H3-specific reader protein, in AZA-sensitive cells after treatment, whereas AZA treatment did not affect HP1 family proteins in AZA-resistant cells. The expression of shRNA targeting HP1γ reduced viability and induced apoptosis specifically in AZA-resistant cells, which accompanied with down-regulation of ATM/BRCA1 signaling, indicating that chromatin regulation by HP1γ plays a key role in the survival of AZA-resistant cells. In addition, the amount of HP1γ protein in AZA-sensitive and AZA-resistant cells was decreased after treatment with the bromodomain inhibitor I-BET151 at a dose that inhibited the growth of AZA-resistant cells more strongly than that of AZA-sensitive cells. Our findings demonstrate that treatment with AZA, which affects an epigenetic reader protein and targets HP1γ, or a bromodomain inhibitor is a novel strategy that can be used to treat patients with hematopoietic neoplasms with AZA resistance.
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影响因子：
21.3
作者：
Lomberk, G;Bensi, D;Urrutia, R
通讯作者：
Urrutia, R
影响因子：
30.8
作者：
Fuks, F;Burgers, WA;Kouzarides, T
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Kouzarides, T
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16
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Vakoc, CR;Mandat, SA;Blobel, GA
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Blobel, GA
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64.8
作者：
Viré, E;Brenner, C;Fuks, F
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Fuks, F
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4.6
作者：
Tsujioka T;Yokoi A;Itano Y;Takahashi K;Ouchida M;Okamoto S;Kondo T;Suemori S;Tohyama Y;Tohyama K
通讯作者：
Tohyama K