Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Science, Houston, TX 77030, USA.
Cell Rep. 2018 Apr 17;23(3):823-837. doi: 10.1016/j.celrep.2018.03.078.
Although EZH2 enzymatic inhibitors have shown antitumor effects in EZH2-mutated lymphoma and ARID1A-mutated ovarian cancer, many cancers do not respond because EZH2 can promote cancer independently of its histone methyltransferase activity. Here we identify ZRANB1 as the EZH2 deubiquitinase. ZRANB1 binds, deubiquitinates, and stabilizes EZH2. Depletion of ZRANB1 in breast cancer cells results in EZH2 destabilization and growth inhibition. Systemic delivery of ZRANB1 small interfering RNA (siRNA) leads to marked antitumor and antimetastatic effects in preclinical models of triple-negative breast cancer (TNBC). Intriguingly, a small-molecule inhibitor of ZRANB1 destabilizes EZH2 and inhibits the viability of TNBC cells. In patients with breast cancer, ZRANB1 levels correlate with EZH2 levels and poor survival. These findings suggest the therapeutic potential for targeting the EZH2 deubiquitinase ZRANB1.
尽管 EZH2 酶抑制剂在 EZH2 突变淋巴瘤和 ARID1A 突变卵巢癌中显示出抗肿瘤作用，但许多癌症没有反应，因为 EZH2 可以独立于其组蛋白甲基转移酶活性促进癌症。在这里，我们确定 ZRANB1 为 EZH2 的去泛素化酶。ZRANB1 结合、去泛素化和稳定 EZH2。ZRANB1 在乳腺癌细胞中的耗竭导致 EZH2 不稳定和生长抑制。ZRANB1 小干扰 RNA (siRNA) 的系统递送导致三阴性乳腺癌 (TNBC) 的临床前模型中明显的抗肿瘤和抗转移作用。有趣的是，ZRANB1 的小分子抑制剂使 EZH2 不稳定并抑制 TNBC 细胞的活力。在乳腺癌患者中，ZRANB1 水平与 EZH2 水平和不良预后相关。这些发现表明靶向 EZH2 去泛素化酶 ZRANB1 的治疗潜力。
