PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα
PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα
复制标题
PRMT5 介导的 RNF4 甲基化通过稳定癌蛋白 PML-RARα 促进 APL 细胞对 As2O3 的治疗耐药性
DOI：
10.1007/s00018-022-04358-3
复制
发表时间：
2022-06-01
影响因子：
8
通讯作者：
Zheng，Xiaofeng
中科院分区：
文献类型：
--
作者：
Huang，Xinping;Yang，Yongfeng;Zheng，Xiaofeng
急性早幼粒细胞白血病是一种由原癌蛋白PML-RARα引起的血液系统恶性肿瘤，可用三氧化二砷或/和全反式维甲酸治疗。精氨酸甲基转移酶5(PRMT5)蛋白参与肿瘤的发生。然而，目前对PRMT5在APL中的生物学功能和治疗潜力知之甚少。在这里，我们发现PRMT5在APL患者中高度表达。PrMT5通过与PML-RARα相互作用，抑制其泛素化和降解，从而促进APL。在机制上，PrMT5通过使RNF4在Arg164位甲基化来减弱PML-RARα与其泛素E3连接酶RNF4之间的相互作用。值得注意的是，As_2O_3处理触发了PrMT5从PML核体中解离，减弱了RNF4的甲基化，并促进了RNF4介导的PML-RARα的泛素化和降解。此外，特异性抑制剂EPZ015666下调PRMT5和药物抑制PRMT5可显著抑制APL细胞的生长。EPZ015666与As_2O_3联合应用对As_2O_3诱导的APL小鼠骨髓细胞分化以及APL患者原代APL细胞的凋亡和分化均有协同作用。这些发现从机制上深入了解了PRMT5在APL发病机制中的作用，并证明了单独或与三氧化二砷联合抑制PRMT5可能是一种有前途的APL治疗策略。
Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (As2O3) or/and all-trans retinoic acid. The protein arginine methyltransferase 5 (PRMT5) is involved in tumorigenesis. However, little is known about the biological function and therapeutic potential of PRMT5 in APL. Here, we show that PRMT5 is highly expressed in APL patients. PRMT5 promotes APL by interacting with PML-RARα and suppressing its ubiquitination and degradation. Mechanistically, PRMT5 attenuates the interaction between PML-RARα and its ubiquitin E3 ligase RNF4 by methylating RNF4 at Arg164. Notably, As2O3treatment triggers the dissociation of PRMT5 from PML nuclear bodies, attenuating RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Moreover, knockdown of PRMT5 and pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 significantly inhibit APL cells growth. The combination of EPZ015666 with As2O3shows synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with As2O3, might be a promising therapeutic strategy against APL.