SUMOylation inhibition enhances dexamethasone sensitivity in multiple myeloma.
SUMOylation inhibition enhances dexamethasone sensitivity in multiple myeloma.
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DOI：
10.1186/s13046-021-02226-9
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发表时间：
2022-01-04
期刊：
影响因子：
--
通讯作者：
Rosen ST
中科院分区：
文献类型：
--
作者：
Du L;Liu W;Aldana-Masangkay G;Pozhitkov A;Pichiorri F;Chen Y;Rosen ST
多发性骨髓瘤(MM)是一种无法治愈的浆细胞恶性肿瘤。虽然地塞米松(Dex)是治疗多发性骨髓瘤(MM)中使用最广泛的治疗药物，但患者对地塞米松的耐药性会导致疾病的进展，迫切需要研究地塞米松耐药的机制，并开发新的试剂来解决这一问题。我们认为SUMO化是调节地塞米松抵抗的一个潜在机制，SUMO化抑制可以提高MM对地塞米松的敏感性。使用MM细胞株和复发性MM患者的原代MM标本，我们评估了抑制SUMO E1(SAE2)或使用一种新的特异性SUMO E1抑制剂TAK-981对地塞米松敏感性的影响。建立小鼠移植瘤模型，观察TAK-981作为单药及与地塞米松合用的体内抗MM作用。利用miRNA-seq、RNA-seq和GSEA分析评价了介导地塞米松抗性的关键因素。染色质免疫沉淀(ChIP)法检测c-Myc在miRs启动子区域的结合占有率。我们观察到在原发多发性骨髓瘤标本中，SAE2的表达与地塞米松敏感性呈显著负相关。敲除SAE2或使用TAK-981可显著增强MM细胞系对地塞米松的敏感性。此外，TAK-981和地塞米松联合应用于复发性多发性骨髓瘤患者样本和异种移植小鼠模型，证实了其增强的抗多发性骨髓瘤活性。糖基化抑制通过下调miR-130b增加糖皮质激素受体(GR)的表达。通过RNA和microRNA测序，我们确定miR-551b和miR-25是介导MM对地塞米松耐药的重要miR。miR-551b和miR-25的过表达导致了对地塞米松的抗性，而miR-551b和miR-25的敲除显著增强了MM对地塞米松的敏感性。SAE2基因敲除或TAK-981处理下调了miR-551b和miR-25的表达，导致诱导miR靶点ZFP36、ULK1和p27，导致细胞凋亡和自噬。我们证明c-Myc是miR-130b、miR-551b和miR-25的主要转录激活剂，SUMO化抑制通过降低c-Myc水平来下调这些miRs水平。我们的研究证明SUMO化在MM的地塞米松耐药中起关键作用，抑制SUMO化似乎是一种有吸引力的策略，有望推动MM患者的临床应用。网上版载有补充材料，可在10.1186/s13046-021-02226-9查阅。
Multiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms driving Dex resistance and develop new reagents to address this problem. We propose SUMOylation as a potential mechanism regulating Dex resistance and SUMOylation inhibition can enhance Dex sensitivity in MM. Using MM cell lines and primary MM samples from relapsing MM patients, we evaluated the effects of knockdown of SUMO E1 (SAE2) or using TAK-981, a novel and specific SUMO E1 inhibitor, on Dex sensitivity. Xenograft mouse models were generated to determine the in vivo anti-MM effects of TAK-981 as a single agent and in combination with Dex. miRNA-seq, RNA-seq and GSEA analysis were utilized for evaluating key factors mediating Dex resistance. Chromatin immunoprecipitation (ChIP) assay was performed to determine the binding occupancy of c-Myc on promoter region of miRs. We observed a significant negative correlation between SUMO E1 (SAE2) expression and Dex sensitivity in primary MM samples. Knockdown of SAE2 or using TAK-981 significantly enhances myeloma sensitivity to Dex in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Dex combination has been validated using primary relapsing MM patient samples and xenograft mouse models. SUMOylation inhibition increased glucocorticoid receptor (GR) expression via downregulation miR-130b. Using RNA and microRNA sequencing, we identified miR-551b and miR-25 as important miRs mediating Dex resistance in MM. Overexpression of miR-551b and miR-25 caused resistance to Dex, however, knockdown of miR-551b and miR-25 significantly enhanced Dex sensitivity in MM. SAE2 knockdown or TAK-981 treatment downregulated the expression of miR-551b and miR-25, leading to induction of miR targets ZFP36, ULK1 and p27, resulting in apoptosis and autophagy. We demonstrated c-Myc as a major transcriptional activator of miR-130b, miR-551b and miR-25 and SUMOylation inhibition downregulates these miRs level by decreasing c-Myc level. Our study proves SUMOylation plays a crucial role in Dex resistance in MM and SUMOylation inhibition appears to be an attractive strategy to advance to the clinic for MM patients. The online version contains supplementary material available at 10.1186/s13046-021-02226-9.
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影响因子：
11.2
作者：
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通讯作者：
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8.8
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通讯作者：
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