The histone acetyltransferase HBO1 functions as a novel oncogenic gene in osteosarcoma.
The histone acetyltransferase HBO1 functions as a novel oncogenic gene in osteosarcoma.
复制标题
组蛋白乙酰转移酶 HBO1 在骨肉瘤中发挥新型致癌基因的作用
作者：
Gao YY;Ling ZY;Zhu YR;Shi C;Wang Y;Zhang XY;Zhang ZQ;Jiang Q;Chen MB;Yang S;Cao C
HBO 1（KAT 7或MYST 2）是一种乙酰化H3和H4组蛋白的组蛋白乙酰转移酶。方法：检测人骨肉瘤组织和细胞中HBO 1的表达。应用包括shRNA、CRISPR/Cas9和过表达构建体的遗传策略来外源性改变OS细胞中的HBO 1表达。HBO 1抑制剂WM-3835用于阻断HBO 1活化。结果：HBO 1 mRNA和蛋白在骨肉瘤组织和细胞中的表达均明显升高。在已建立的（MG 63/U2 OS系）和原代人OS细胞中，shRNA介导的HBO 1沉默和CRISPR/Cas9诱导的HBO 1敲除能够有效抑制细胞活力、生长、增殖以及细胞迁移和侵袭。在HBO 1沉默/敲除的OS细胞中检测到凋亡的显著增加。相反，异位HBO 1过表达促进OS细胞增殖和迁移。我们确定ZNF 384（zinc finger protein 384）为HBO 1的潜在转录因子。在OS细胞和组织中检测到ZNF 384与HBO 1启动子之间的结合增加，而ZNF 384通过shRNA沉默下调HBO 1并产生显著的抗OS细胞活性。在体内，肿瘤内注射HBO 1 shRNA慢病毒沉默HBO 1并抑制小鼠OS异种移植物生长。此外，HBO 1敲除OS异种移植物的生长显著慢于对照异种移植物。WM-3835是一种新型的高特异性的小分子HBO 1抑制剂，能够有效地抑制OS细胞的增殖和迁移，并导致凋亡激活。此外，腹膜内注射单剂量WM-3835可有效抑制SCID小鼠中OS异种移植物生长。结论：HBO 1过表达可促进OS细胞的生长。
HBO1 (KAT7 or MYST2) is a histone acetyltransferase that acetylates H3 and H4 histones. Methods: HBO1 expression was tested in human OS tissues and cells. Genetic strategies, including shRNA, CRISPR/Cas9 and overexpression constructs, were applied to exogenously alter HBO1 expression in OS cells. The HBO1 inhibitor WM-3835 was utilized to block HBO1 activation. Results: HBO1 mRNA and protein expression is significantly elevated in OS tissues and cells. In established (MG63/U2OS lines) and primary human OS cells, shRNA-mediated HBO1 silencing and CRISPR/Cas9-induced HBO1 knockout were able to potently inhibit cell viability, growth, proliferation, as well as cell migration and invasion. Significant increase of apoptosis was detected in HBO1-silenced/knockout OS cells. Conversely, ectopic HBO1 overexpression promoted OS cell proliferation and migration. We identified ZNF384 (zinc finger protein 384) as a potential transcription factor of HBO1. Increased binding between ZNF384 and HBO1 promoter was detected in OS cell and tissues, whereas ZNF384 silencing via shRNA downregulated HBO1 and produced significant anti-OS cell activity. In vivo, intratumoral injection of HBO1 shRNA lentivirus silenced HBO1 and inhibited OS xenograft growth in mice. Furthermore, growth of HBO1-knockout OS xenografts was significantly slower than the control xenografts. WM-3835, a novel and high-specific small molecule HBO1 inhibitor, was able to potently suppressed OS cell proliferation and migration, and led to apoptosis activation. Furthermore, intraperitoneal injection of a single dose of WM-3835 potently inhibited OS xenograft growth in SCID mice. Conclusion: HBO1 overexpression promotes OS cell growth in vitro and in vivo.
登录
查看更多内容
DOI：
10.1038/modpathol.2017.125
发表时间：
2018-03
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
Chaiyawat P;Pruksakorn D;Phanphaisarn A;Teeyakasem P;Klangjorhor J;Settakorn J
通讯作者：
Settakorn J
microRNA-19a 通过靶向 TSC1 保护成骨细胞免受地塞米松的影响
影响因子：
--
作者：
Liu G;Chen FL;Ji F;Fei HD;Xie Y;Wang SG
通讯作者：
Wang SG
影响因子：
7.2
作者：
Chen, M;Wang, J
通讯作者：
Wang, J
影响因子：
4.8
作者：
Burke, TW;Cook, JG;Nevins, JR
通讯作者：
Nevins, JR
评估GSK1904529A作为有前途的抗骨肉瘤剂。
影响因子：
--
作者：
Fei HD;Yuan Q;Mao L;Chen FL;Cui ZH;Tao S;Ji F
通讯作者：
Ji F