Department of Pediatrics, Xinyi people's Hospital, Xinyi, China.
Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, China.
Theranostics. 2021 Mar 4;11(10):4599-4615. doi: 10.7150/thno.55655. eCollection 2021.
HBO1 (KAT7 or MYST2) is a histone acetyltransferase that acetylates H3 and H4 histones. 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. 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. , 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. HBO1 overexpression promotes OS cell growth and
HBO1（KAT7 或 MYST2）是一种组蛋白乙酰转移酶，可乙酰化 H3 和 H4 组蛋白。在人 OS 组织和细胞中检测到 HBO1 表达。应用包括 shRNA、CRISPR/Cas9 和过表达构建体在内的遗传策略，在外源性改变 OS 细胞中的 HBO1 表达。利用 HBO1 抑制剂 WM-3835 阻断 HBO1 激活。OS 组织和细胞中的 mRNA 和蛋白表达显著升高。在已建立（MG63/U2OS 系）和原代人 OS 细胞中，shRNA 介导的 HBO1 沉默和 CRISPR/Cas9 诱导的 HBO1 敲除能够强烈抑制细胞活力、生长、增殖以及细胞迁移和侵袭。在 HBO1 沉默/敲除的 OS 细胞中检测到明显的细胞凋亡增加。相反，外源性 HBO1 过表达促进了 OS 细胞的增殖和迁移。我们鉴定出 ZNF384（锌指蛋白 384）是 HBO1 的潜在转录因子。在 OS 细胞和组织中检测到 ZNF384 与 HBO1 启动子之间的结合增加，而通过 shRNA 沉默 ZNF384 则下调了 HBO1，并产生了显著的抗 OS 细胞活性。在体内，HBO1 shRNA 慢病毒的肿瘤内注射沉默了 HBO1 并抑制了小鼠中的 OS 异种移植物生长。此外，HBO1 敲除 OS 异种移植物的生长速度明显慢于对照异种移植物。新型高特异性小分子 HBO1 抑制剂 WM-3835 能够强烈抑制 OS 细胞增殖和迁移，并导致凋亡激活。此外，单次腹腔注射 WM-3835 能够强烈抑制 SCID 小鼠中的 OS 异种移植物生长。HBO1 过表达促进 OS 细胞生长。
