Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma
Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma
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缺氧通过协调多发性骨髓瘤中 SRC-3 的去SUMO化和泛素化诱导对蛋白酶体抑制剂的化学耐药性
DOI：
10.1038/s41388-022-02494-5
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发表时间：
2022-10
期刊：
影响因子：
8
通讯作者：
Zhiqiang Liu
中科院分区：
文献类型：
--
作者：
Jing Guo;Yangyang Lv;Sheng Wang;Ziyi Peng;Ying Xie;Yixuan Wang;Hongmei Jiang;Xin Li;Mengqi Wang;Meilin Hu;Jiangpeng Mu;Jingya Wang;Yangyang Xie;Xiankui Cheng;Zhigang Zhao;Zhiqiang Liu
多发性骨髓瘤(MM)的骨髓微环境是低氧的，并为化疗耐药的启动提供了多种有利条件，但其潜在机制和关键调控因素仍不清楚。在目前的研究中，我们发现低氧刺激容易诱导对蛋白酶体抑制剂(PIs)的化疗耐药，并且类固醇受体辅活化子3(SRC-3)的表达在翻译后水平显著增强。蛋白质相互作用组分析发现SENP1是SRC-3稳定性的关键修饰物，因为SENP1介导的去SUMO减弱了K11连锁的SRC-3的多泛素化。SENP1fl/flCD19Cre/+B细胞中SENP1的缺失表现出SRC3稳定性降低，而CRISPR/Cas9 sgRNA敲除MM细胞中的SENP1加速了SRC-3的降解，并显著克服了对PI的耐药性。在VK*Myc和5TGM1小鼠模型以及患者来源的骨髓瘤移植瘤模型中，SENP1抑制剂MomordinΙc(Mc)增加了MM细胞对PI的敏感性。重要的是，在难治性/复发性多发性骨髓瘤组织中，SENP1水平与SRC-3水平呈正相关，在接受硼替佐米和Mc治疗的异种移植组织中，SENP1水平与SRC-3水平正相关。综上所述，我们的研究结果表明，低氧诱导的SENP1是PI化疗耐药的关键调节因子，并为开发通过靶向SENP1或SRC-3的小分子来克服化疗耐药的治疗策略奠定了基础。
The bone marrow microenvironment in multiple myeloma (MM) is hypoxic and provides multi-advantages for the initiation of chemoresistance, but the underlying mechanisms and key regulators are still indistinct. In the current study, we found that hypoxia stimulus easily induced chemoresistance to proteasome inhibitors (PIs), and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein interactome analysis identified SENP1 as a key modifier of SRC-3 stability, as SENP1-mediated deSUMOylation attenuated the K11-linked polyubiquitination of SRC-3. SENP1 depletion in the SENP1fl/flCD19Cre/+B cells showed impaired SRC3 stability, and knockdown ofSENP1in MM cells by CRISPR/cas9 sgRNA accelerated the degradation of SRC-3 and remarkably overcame the resistance to PIs. In the Vk*Myc and 5TGM1 mouse models as well as patient-derived xenograft (PDX) of myeloma, SENP1 inhibitor Momordin Ιc (Mc) increased the sensitivity to PIs in MM cells. Importantly, SENP1 level was positively correlated with SRC-3 level in the tissues from refractory/relapsed MM, as well as in xenograft tissues from mice treated with bortezomib and Mc. Taken together, our findings suggest that hypoxia-induced SENP1 is a crucial regulator of chemoresistance to PIs, and shed light on developing therapeutic strategies to overcome chemoresistance by using small molecules targeting SENP1 or SRC-3.
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DOI：
10.1182/asheducation-2004.1.237
发表时间：
1997
期刊：
The New England journal of medicine
影响因子：
--
作者：
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通讯作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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Liu J;Xie Y;Guo J;Li X;Wang J;Jiang H;Peng Z;Wang J;Wang S;Li Q;Ye L;Zhong Y;Zhang Q;Liu X;Lonard DM;Wang J;O'Malley BW;Liu Z
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