Parker Kyra, Zhang Yanfeng, Anchondo Gavin, Smith Ashlyn, Guerrero Pacheco Sergio, Kondo Tadashi, Su Le
Department of Biology, Jacksonville State University, Jacksonville, AL, United States.
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, United States.
Front Cell Dev Biol. 2024 Jul 9;12:1422452. doi: 10.3389/fcell.2024.1422452. eCollection 2024.
The SS18-SSX fusion protein is an oncogenic driver in synovial sarcoma. At the molecular level, SS18-SSX functions as both an activator and a repressor to coordinate transcription of different genes responsible for tumorigenesis. Here, we identify the proto-oncogene as a new SS18-SSX target gene and examine its relation to synovial sarcoma therapy. FYN is a tyrosine kinase that promotes cancer growth, metastasis and therapeutic resistance, but SS18-SSX appears to negatively regulate expression in synovial sarcoma cells. Using both genetic and histone deacetylase inhibitor (HDACi)-based pharmacologic approaches, we show that suppression of SS18-SSX leads to reactivation. In support of this notion, we find that blockade of FYN activity synergistically enhances HDACi action to reduce synovial sarcoma cell proliferation and migration. Our results support a role for FYN in attenuation of anti-cancer activity upon inhibition of SS18-SSX function and demonstrate the feasibility of targeting FYN to improve the effectiveness of HDACi treatment against synovial sarcoma.
SS18-SSX融合蛋白是滑膜肉瘤中的致癌驱动因子。在分子水平上，SS18-SSX既作为激活剂又作为抑制剂来协调负责肿瘤发生的不同基因的转录。在此，我们将原癌基因鉴定为新的SS18-SSX靶基因，并研究其与滑膜肉瘤治疗的关系。FYN是一种酪氨酸激酶，可促进癌症生长、转移和治疗抗性，但SS18-SSX似乎在滑膜肉瘤细胞中对其表达起负调控作用。使用基于遗传和组蛋白去乙酰化酶抑制剂（HDACi）的药理学方法，我们表明抑制SS18-SSX会导致FYN重新激活。支持这一观点的是，我们发现阻断FYN活性可协同增强HDACi的作用，以减少滑膜肉瘤细胞的增殖和迁移。我们的结果支持FYN在抑制SS18-SSX功能后对抗癌活性的减弱中所起的作用，并证明了靶向FYN以提高HDACi治疗滑膜肉瘤有效性的可行性。
