Abstract：
The ubiquitin-proteasome system (UPS), which involves E3 ligases and deubiquitinates (DUBs), is critical for protein homeostasis. The epigenetic reader ZMYND8 (zinc finger MYND-type containing 8) has emerged as an oncoprotein, and its protein levels are elevated in various types of cancer, including breast cancer. However, the mechanism by which ZMYND8 protein levels are increased in cancer remains elusive. Although ZMYND8 has been reported to be regulated by the E3 ligase FBXW7, it is still unknown whether ZMYND8 could be modulated by DUBs. Here, we identified USP7 (ubiquitin carboxyl-terminal hydrolase 7) as a bona fide DUB for ZMYND8. Mechanically, USP7 directly binds to the PBP (PHD-BRD-PWWP) domain of ZMYND8 via its TRAF (tumor necrosis factor receptor-associated factor) domain and UBL (ubiquitin-like) domain and removes F-box and WD repeat domain containing 7 (FBXW7)-catalyzed poly-ubiquitin chains on lysine residue 1034 (K1034) within ZMYND8, thereby stabilizing ZMYND8 and stimulating the transcription of ZMYND8 target genes ZEB1 (zinc finger E-box binding homeobox 1) and VEGFA (Vascular Endothelial Growth Factor A). Consequently, USP7 enhances the capacity of breast cancer cells for migration and invasion through antagonizing FBXW7-mediated ZMYND8 degradation. Importantly, the protein levels of USP7 positively correlates with those of ZMYND8 in breast cancer tissues. These findings delineate an important layer of migration and invasion regulation by the USP7-ZMYND8 axis in breast cancer cells.
摘要：
泛素-蛋白酶体系统（UPS），涉及E3连接酶和去泛素酶（DUB），对蛋白质稳态至关重要。表观遗传学阅读器ZMYND8（含8个锌指MYND型）已成为癌蛋白，其蛋白质水平在各种类型的癌症中升高，包括乳腺癌.然而,癌症中ZMYND8蛋白水平升高的机制仍然难以捉摸.尽管据报道ZMYND8受E3连接酶FBXW7调节，但仍不清楚ZMYND8是否可被DUB调节。这里,我们确定USP7（泛素羧基末端水解酶7）是ZMYND8的真正DUB。机械上,USP7通过其TRAF（肿瘤坏死因子受体相关因子）结构域和UBL（泛素样）结构域直接结合ZMYND8的PBP（PHD-BRD-PWWP）结构域，并去除含有7个（FBXW7）催化的多泛素链在ZMYND8内的赖氨酸残基1034（K1034）上的泛素链，从而稳定ZMYNDA和VEGA-Z因此,USP7通过拮抗FBXW7介导的ZMYND8降解增强乳腺癌细胞迁移和侵袭的能力。重要的是,乳腺癌组织中USP7的蛋白质水平与ZMYND8的蛋白质水平正相关。这些发现描绘了乳腺癌细胞中USP7-ZMYND8轴的重要迁移和侵袭调节层。
