Guo Mengjie, Ding Pinggang, Zhu Zhen, Fan Lu, Zhou Yanyan, Yang Shu, Yang Ye, Gu Chunyan
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Large Data Center, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
Front Cell Dev Biol. 2021 Apr 21;9:675939. doi: 10.3389/fcell.2021.675939. eCollection 2021.
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. 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, 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.
在多发性骨髓瘤（MM）治疗过程中，克服对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。组成型光形态建成1（RFWD2），一种E3泛素连接酶，已被确定为多种癌症中的致癌基因，但关于RFWD2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，RFWD2表达升高的MM患者预后不良且具有耐药性。此外，我们通过质谱分析证明RFWD2参与了MM的细胞周期、细胞生长和死亡过程。研究表明，诱导敲低RFWD2会阻碍MM细胞的生长并引发细胞凋亡。机制研究表明，RFWD2通过调节P27而非P53的降解来控制MM细胞增殖。进一步的探索发现，RFWD2通过与作为P27的E3泛素连接酶的RCHY1相互作用来介导P27的泛素化。最后，研究表明在BTZ耐药的MM细胞中阻断RFWD2可在骨髓瘤异种移植小鼠模型中克服耐药性。综上所述，这些发现为提示靶向RFWD2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提供了有力证据。
