Kotani Yuki, Imura Yoshinori, Nakai Sho, Chijimatsu Ryota, Takami Haruna, Inoue Akitomo, Mae Hirokazu, Takenaka Satoshi, Outani Hidetatsu, Okada Seiji
Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan.
Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
Cancers (Basel). 2024 Mar 11;16(6):1125. doi: 10.3390/cancers16061125.
Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines. Notably, BET inhibitors exhibited regulatory control over crucial cell-cycle regulators, such as MYC, p21, CDK4, and CDK6. Additionally, RNA sequencing findings across the four cell lines revealed the significance of fluctuating BCL2 family protein expression during apoptotic induction. Notably, variations in the expression ratio of the anti-apoptotic factor BCLxL and the pro-apoptotic factor BIM may underlie susceptibility to ABBV-075. Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS.
滑膜肉瘤（SS）是一种罕见的软组织肉瘤亚型，以融合基因SS18 - SSX的表达为特征，主要影响年轻患者的四肢。现有的抗癌药物对这种恶性肿瘤的疗效有限，因此需要开发创新的治疗方法。鉴于SS18 - SSX在表观遗传调控中的既定作用，我们将重点放在了溴结构域和额外末端结构域蛋白（BET）抑制剂及表观遗传药物上。我们对BET抑制剂ABBV - 075的研究表明，它在四种SS细胞系中具有显著的抗肿瘤作用，可诱导G1期细胞周期停滞和凋亡。值得注意的是，BET抑制剂对关键的细胞周期调节因子，如MYC、p21、CDK4和CDK6具有调控作用。此外，对这四种细胞系的RNA测序结果显示，在凋亡诱导过程中，BCL2家族蛋白表达的波动具有重要意义。值得注意的是，抗凋亡因子BCLxL与促凋亡因子BIM的表达比例变化可能是对ABBV - 075敏感性的基础。此外，上调BCL2的SS18 - SSX基因敲低降低了对ABBV - 075的敏感性。这些发现表明，靶向SS18 - SSX调控的内在凋亡途径的BET抑制剂作为一种有前景的SS治疗策略具有潜在的应用价值。
