Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma.
Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma.
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DOI：
10.3389/fcell.2021.675939
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发表时间：
2021
影响因子：
5.5
通讯作者：
Gu C
中科院分区：
文献类型：
--
作者：
Guo M;Ding P;Zhu Z;Fan L;Zhou Y;Yang S;Yang Y;Gu C
在多发性骨髓瘤（MM）治疗过程中，克服蛋白酶体抑制剂耐药性的潜力与泛素-蛋白酶体系统密切相关。组成型光形态发生1（RFWD 2），称为E3泛素连接酶，已被确定为多种癌症中的癌基因，但关于RFWD 2在MM生物学和治疗中的作用的重要问题仍不清楚。在这里，我们通过分析基因表达谱证明了RFWD 2表达升高的MM患者会出现不良结局和耐药性。此外，我们还通过质谱分析证明RFWD 2参与了MM细胞周期、细胞生长和死亡的过程。体外研究表明，RFWD 2的可诱导敲低阻碍了MM细胞的生长并触发了MM细胞的凋亡。机制研究表明RFWD 2通过调节P27而非P53的降解来控制MM细胞的增殖。进一步的研究发现RFWD 2通过与RCHY 1相互作用介导P27的泛素化，RCHY 1是P27的E3泛素连接酶。最后，体内研究表明，阻断BTZ抗性MM细胞中的RFWD 2克服了骨髓瘤异种移植小鼠模型中的耐药性。总之，这些发现提供了令人信服的证据，提示靶向RFWD 2可能是抑制MM细胞增殖和克服对蛋白酶体抑制剂耐药性的有效策略。
The potential to overcome resistance to proteasome inhibitors is greatly related with ubiquitin-proteasome system during multiple myeloma (MM) treatment process. The constitutive photomorphogenic 1 (RFWD2), referred to an E3 ubiquitin ligase, has been identified as an oncogene in multiple cancers, yet important questions on the role of RFWD2 in MM biology and treatment remain unclear. Here we demonstrated that MM patients with elevated RFWD2 expression achieved adverse outcome and drug resistance by analyzing gene expression profiling. Moreover, we proved that RFWD2 participated in the process of cell cycle, cell growth and death in MM by mass spectrometry analysis. In vitro study indicated that inducible knockdown of RFWD2 hindered cellular growth and triggered apoptosis in MM cells. Mechanism study revealed that RFWD2 controlled MM cellular proliferation via regulating the degradation of P27 rather than P53. Further exploration unveiled that RFWD2 meditated P27 ubiquitination via interacting with RCHY1, which served as an E3 ubiquitin ligase of P27. Finally, in vivo study illustrated that blocking RFWD2 in BTZ-resistant MM cells overcame the drug resistance in a myeloma xenograft mouse model. Taken together, these findings provide compelling evidence for prompting that targeting RFWD2 may be an effective strategy to inhibit cellular proliferation and overcome drug resistance to proteasome inhibitor in MM.