Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Mol Carcinog. 2019 Feb;58(2):234-246. doi: 10.1002/mc.22922. Epub 2018 Nov 2.
Undifferentiated pleomorphic sarcoma (UPS) is the second most frequent soft tissue sarcoma. Because of its resistance to chemotherapy, UPS patients are treated with surgical resection and complementary radiotherapy. However, since standard chemotherapy has not been established, unresectable or metastatic cases result in a poor prognosis. Therefore, the identification of a more effective therapy for UPS patients is needed. The development and progression of malignant tumors involve epigenetic alterations, and histone deacetylases (HDAC) have become a promising chemotherapeutic target. In this study, we investigated the potential effects and mechanisms of an HDAC inhibitor, LBH589, in UPS cells. We confirmed that LBH589 exhibits potent antitumor activities in four human UPS cell lines (GBS-1, TNMY-1, Nara-F, and Nara-H) and IC values ranged from 7 to 13 nM. A mouse xenograft model showed that LBH589 treatment effectively suppressed tumor growth. FACS analysis showed that LBH589 induced apoptosis and G2/M cell cycle arrest. Among apoptosis-related proteins, the expressions of Bcl-2 and Bcl-xL were decreased and the expression of Bak and Bim increased. Among cell cycle-related proteins, reductions of CDK1, p-CDK1, cyclin B1, Aurora A, and Aurora B were observed after LBH589 treatment. RNA microarray identified the FOS-like antigen 1 (FOSL1) gene as a downregulated gene in response to LBH589 in UPS cells. While knockdown of FOSL1 decreased UPS cell proliferation, overexpression induced cell proliferation. Our results show that LBH589 could be a promising chemotherapeutic agent in the treatment of UPS and downregulation of the FOSL1 gene could be the new molecular target of UPS treatment.
未分化多形性肉瘤（UPS）是第二常见的软组织肉瘤。由于其对化疗的耐药性，UPS 患者接受手术切除和补充放疗。然而，由于尚未建立标准的化疗方案，不可切除或转移性病例的预后较差。因此，需要为 UPS 患者确定更有效的治疗方法。恶性肿瘤的发生和发展涉及表观遗传改变，组蛋白去乙酰化酶（HDAC）已成为有前途的化疗靶点。在这项研究中，我们研究了 HDAC 抑制剂 LBH589 对 UPS 细胞的潜在作用和机制。我们证实 LBH589 在四种人 UPS 细胞系（GBS-1、TNMY-1、Nara-F 和 Nara-H）中表现出强大的抗肿瘤活性，IC 值范围为 7 至 13 nM。小鼠异种移植模型表明 LBH589 治疗可有效抑制肿瘤生长。FACS 分析表明 LBH589 诱导细胞凋亡和 G2/M 细胞周期停滞。在凋亡相关蛋白中，Bcl-2 和 Bcl-xL 的表达减少，Bak 和 Bim 的表达增加。在细胞周期相关蛋白中，LBH589 处理后观察到 CDK1、p-CDK1、cyclin B1、Aurora A 和 Aurora B 的表达减少。RNA 微阵列鉴定出 FOS 样抗原 1（FOSL1）基因是 UPS 细胞对 LBH589 反应下调的基因。FOSL1 基因敲低降低 UPS 细胞增殖，而过表达诱导细胞增殖。我们的结果表明，LBH589 可能是 UPS 治疗的有前途的化疗药物，下调 FOSL1 基因可能是 UPS 治疗的新分子靶点。
