Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma
Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma
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靶向 Otub1/c-Maf 轴治疗多发性骨髓瘤
DOI：
10.1182/blood.2020005199
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发表时间：
2021-03-18
期刊：
影响因子：
20.3
通讯作者：
Mao, Xinliang
中科院分区：
文献类型：
--
作者：
Xu, Yujia;Xu, Min;Mao, Xinliang
致癌转录因子 c-Maf 已被提议作为多发性骨髓瘤 (MM) 的理想治疗靶点，但如何实现它仍然难以捉摸。在本研究中，我们发现 Otub1/c-Maf 轴可能是一个潜在的目标。通过质谱分析发现 Otub1 是一种 OTU 家族去泛素酶，可与 c-Maf 相互作用。 Otub1 废除 c-Maf K48 连接的多聚泛素化，从而防止其降解并增强其转录活性。具体来说，这种去泛素化活性取决于其 Lys71 和 N 末端，但不依赖于 UBE2O（c-Maf 的已知 E2）。 Otub1 促进 MM 细胞存活和 MM 肿瘤生长。相反，Otub1 的沉默会导致 c-Maf 降解和表达 c-Maf 的 MM 细胞凋亡。因此，Otub1/c-Maf轴可能成为MM的治疗靶点。为了探索这个概念，我们对美国食品和药物管理局批准的药物和天然产物进行了 c-Maf 识别元件驱动的基于荧光素酶的筛选，从中发现通用强心苷毛花苷 C (LanC) 可以防止 c-Maf 去泛素化，并通过破坏 Otub1 和 c-Maf 的相互作用来诱导其降解。因此，LanC 抑制 c-Maf 转录活性，诱导表达 c-Maf 的 MM 细胞凋亡，并抑制 MM 生长并延长模型小鼠的总体生存期，但没有明显的毒性。因此，本研究将 Otub1 确定为 c-Maf 的新型去泛素化酶，并确定 Otub1/c-Maf 轴是 MM 的潜在治疗靶点。
The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element-driven luciferase-based screen against US Food and Drug Administration-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.