Rhabdoid tumor is an aggressive, early childhood tumor. Biallelic inactivation of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)/integrase interactor 1 (INI1) gene is the only common genetic feature in rhabdoid tumors. Loss of SMARCB1 function results in downregulation of several tumor suppressor genes including p16, p21, and NOXA. The novel histone deacetylase inhibitor, OBP-801, induces p21 and has shown efficacy against various cancers. In our study, OBP-801 strongly inhibited the cell growth of all rhabdoid tumor cell lines in WST-8 assay. However, Western blotting and cell-cycle analysis revealed that OBP-801 did not activate the P21-RB pathway in some cell lines. p21 knockout indicated that p21 did not dominate the OBP-801 antitumor effect in rhabdoid tumor cell lines. We discovered that OBP-801 induced NOXA expression and caspase-dependent apoptosis in rhabdoid tumor cell lines independent of TP53. Chromatin immunoprecipitation assay showed that OBP-801 acetylated histone proteins and recruited RNA polymerase II to the transcription start site (TSS) of the NOXA promotor. Moreover, OBP-801 recruited BRG1 and BAF155, which are members of the SWI/SNF complex, to the TSS of the NOXA promotor. These results suggest that OBP-801 epigenetically releases the silencing of NOXA and induces apoptosis in rhabdoid tumors. OBP-801 strongly inhibited tumor growth in human rhabdoid tumor xenograft mouse models in vivo. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and cleaved caspase-3 were stained in tumors treated with OBP-801. In conclusion, OBP-801 induces apoptosis in rhabdoid tumor cells by epigenetically releasing the silencing of NOXA, which is a key mediator of rhabdoid tumor apoptosis. The epigenetic approach for NOXA silencing with OBP-801 is promising for rhabdoid tumor treatment.

中文翻译：

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新型组蛋白去乙酰化酶抑制剂 OBP-801 通过释放 NOXA 的沉默诱导横纹肌瘤细胞凋亡

横纹肌瘤是一种侵袭性的儿童早期肿瘤。染色质亚家族 B 成员 1 (SMARCB1)/整合酶相互作用子 1 (INI1) 基因的 SWI/SNF 相关基质相关肌动蛋白依赖性调节因子的双等位基因失活是横纹肌样瘤中唯一常见的遗传特征。SMARCB1 功能的丧失导致包括 p16、p21 和 NOXA 在内的几种肿瘤抑制基因的下调。新型组蛋白去乙酰化酶抑制剂 OBP-801 可诱导 p21，并已显示出对抗多种癌症的功效。在我们的研究中，OBP-801 在 WST-8 试验中强烈抑制所有横纹肌瘤细胞系的细胞生长。然而，蛋白质印迹和细胞周期分析显示 OBP-801 在某些细胞系中没有激活 P21-RB 通路。p21 敲除表明 p21 在横纹肌瘤细胞系中不主导 OBP-801 抗肿瘤作用。我们发现 OBP-801 在不依赖 TP53 的横纹肌样肿瘤细胞系中诱导 NOXA 表达和半胱天冬酶依赖性细胞凋亡。染色质免疫沉淀试验表明 OBP-801 乙酰化组蛋白并将 RNA 聚合酶 II 募集到 NOXA 启动子的转录起始位点 (TSS)。此外，OBP-801 将 SWI/SNF 复合体的成员 BRG1 和 BAF155 招募到 NOXA 启动子的 TSS。这些结果表明 OBP-801 表观遗传地释放 NOXA 的沉默并诱导横纹肌瘤的细胞凋亡。OBP-801 在体内人横纹肌瘤异种移植小鼠模型中强烈抑制肿瘤生长。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记和裂解的 caspase-3 在用 OBP-801 治疗的肿瘤中染色。综上所述，OBP-801 通过表观遗传释放 NOXA 的沉默来诱导横纹肌瘤细胞凋亡，NOXA 是横纹肌瘤细胞凋亡的关键介质。使用 OBP-801 进行 NOXA 沉默的表观遗传方法有望用于横纹肌样肿瘤治疗。