Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Sci Adv. 2024 Apr 5;10(14):eadj4009. doi: 10.1126/sciadv.adj4009. Epub 2024 Apr 3.
Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 () and promoting the expression of the dominant and oncogenic isoform, . Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.
三阴性乳腺癌（TNBC）是乳腺癌中最致命的亚型，因为缺乏有效的治疗靶点。剪接因子 3a 亚基 2（SF3A2）是一种定义不明确的剪接因子，在 TNBC 组织中明显升高，并通过细胞增殖、集落形成、transwell 迁移和侵袭实验证实促进了 TNBC 的进展。机制研究表明，E3 泛素蛋白连接酶 UBR5 促进 SF3A2 的泛素化依赖性降解，而 SF3A2 反过来又调节 UBR5，从而形成一个反馈环来平衡这两种致癌蛋白。此外，SF3A2 通过至少部分地特异性调节 makorin 环指蛋白 1（）的可变剪接并促进显性致癌同工型的表达，来加速 TNBC 的进展。此外，SF3A2 参与了外在和内在凋亡的调节，导致 TNBC 细胞对顺铂产生耐药性。总的来说，这些发现揭示了 SF3A2 在 TNBC 进展和顺铂耐药性中的一个以前未知的作用，突出了 SF3A2 作为 TNBC 患者潜在治疗靶点的可能性。
