Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Oncogene. 2021 Jan;40(3):578-591. doi: 10.1038/s41388-020-01550-2. Epub 2020 Nov 16.
Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. The survival outcomes remain poor for patients with relapsed or metastatic disease. Effective targeted therapy is lacking due to our limited knowledge of the underlying cellular and molecular mechanisms leading to disease progression. In this study, we used functional assays in vitro and in vivo (zebrafish and xenograft mouse models) to demonstrate the crucial role of HDAC6, a cytoplasmic histone deacetylase, in driving RMS tumor growth, self-renewal, and migration/invasion. Treatment with HDAC6-selective inhibitors recapitulates the HDAC6 loss-of-function phenotypes. HDAC6 regulates cytoskeletal dynamics to promote tumor cell migration and invasion. RAC1, a Rho family GTPase, is an essential mediator of HDAC6 function, and is necessary and sufficient for RMS cell migration and invasion. High expression of RAC1 correlates with poor clinical prognosis in RMS patients. Targeting the HDAC6-RAC1 axis represents a promising therapeutic option for improving survival outcomes of RMS patients.
横纹肌肉瘤（RMS）是一种严重的儿科肉瘤。对于复发或转移性疾病的患者，其生存结果仍然较差。由于我们对导致疾病进展的潜在细胞和分子机制的了解有限，因此缺乏有效的靶向治疗。在这项研究中，我们使用体外和体内（斑马鱼和异种移植小鼠模型）功能测定来证明细胞质组蛋白去乙酰化酶 HDAC6 在驱动 RMS 肿瘤生长、自我更新以及迁移/侵袭中的关键作用。用 HDAC6 选择性抑制剂处理可重现 HDAC6 功能丧失表型。HDAC6 调节细胞骨架动力学以促进肿瘤细胞迁移和侵袭。RAC1，一种 Rho 家族 GTPase，是 HDAC6 功能的重要介质，对于 RMS 细胞的迁移和侵袭是必需且充分的。RAC1 的高表达与 RMS 患者的不良临床预后相关。靶向 HDAC6-RAC1 轴代表改善 RMS 患者生存结果的有前途的治疗选择。
