Sun Kai, Yang Lu, Wang Feng, Liu Ying, Xu Nan, Shi Zong-Yan, Chen Wen-Min, Li Ke, Qin Ya-Zhen
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, PR China.
Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
Heliyon. 2024 Jul 4;10(13):e34094. doi: 10.1016/j.heliyon.2024.e34094. eCollection 2024 Jul 15.
Multiple myeloma (MM) is a Ubiquitin Proteasome System (UPS)-dysfunction disease. We previously reported that high transcript levels associated with unfavorable progression free survival (PFS) in patients with no bortezomib therapy, and bortezomib-containing regimen significantly improved PFS in patients with high transcript levels, which indicated that expression was prognostic for MM patients, and was related to proteasome inhibitor treatment. However, molecular mechanisms underlying the above clinical performance remain unclear. In the present study, MM cell models with knockdown and overexpression were established, and was identified to play the role of promoting proliferation in MM cells. P-Akt signaling was found to be activated as overexpressed. As a substrate recognizing subunit (SRS) of the E3 ubiquitin ligase, PRAME targets substrate proteins and mediates their degradation. CTMP and p21 were found to be the novel targets of PRAME in the Cul2-dependent substrate recognition process. PRAME interacted with and mediated ubiquitination and degradation of CTMP and p21, which led to accumulation of -Akt and CCND3 proteins, and thus promoted cell proliferation and increased bortezomib sensitivity in MM cells.
多发性骨髓瘤（MM）是一种泛素蛋白酶体系统（UPS）功能障碍性疾病。我们之前报道过，在未接受硼替佐米治疗的患者中，高转录水平与不良无进展生存期（PFS）相关，而含硼替佐米的方案显著改善了高转录水平患者的PFS，这表明[此处原文缺失具体基因名称]表达对MM患者具有预后意义，且与蛋白酶体抑制剂治疗相关。然而，上述临床表型背后的分子机制仍不清楚。在本研究中，建立了[此处原文缺失具体基因名称]敲低和过表达的MM细胞模型，并确定[此处原文缺失具体基因名称]在MM细胞中发挥促进增殖的作用。发现随着[此处原文缺失具体基因名称]过表达，P-Akt信号被激活。作为E3泛素连接酶的底物识别亚基（SRS），PRAME靶向底物蛋白并介导其降解。发现CTMP和p21是PRAME在Cul2依赖性底物识别过程中的新靶点。PRAME与CTMP和p21相互作用并介导其泛素化和降解，导致-Akt和CCND3蛋白积累，从而促进MM细胞增殖并增加硼替佐米敏感性。
