Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma
Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma
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蛋白酶体抑制剂诱导 SIRT1 使 GLI2 去乙酰化，增强多发性骨髓瘤中的 hedgehog 信号活性和耐药性
DOI：
10.1038/s41388-019-1037-6
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发表时间：
2020-01-01
期刊：
影响因子：
8
通讯作者：
Liu, Zhiqiang
中科院分区：
文献类型：
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作者：
Xie, Ying;Liu, Jing;Liu, Zhiqiang
尽管蛋白酶体抑制剂在临床上的成功应用，多发性骨髓瘤（MM）仍然是无法治愈的。硼替佐米是MM最常见的化疗方案，而获得性耐药和最终复发仍然是主要障碍。在目前的研究中，我们建立了抗硼替佐米骨髓瘤细胞系，并使用单细胞rna测序筛选基因表达谱。耐药MM细胞表现出增加的克隆生成潜力、特定的代谢和表观遗传特征，以及MM干细胞样细胞的自我更新信号特征。hedgehog （Hh）信号的异常激活与耐药和干细胞样转录程序相关。在硼替佐米耐药骨髓瘤细胞中，Hh通路的关键转录因子GLI2在高乙酰化和低泛素化状态下受到限制。进一步的研究表明SIRT1在赖氨酸757处使GLI2蛋白去乙酰化并稳定，从而激活Hh信号传导，并且SIRT1本身作为Hh信号传导的直接靶点形成一个正调控环。通过表观遗传化合物文库联合筛选，我们发现SIRT1特异性抑制剂S1541和S2804具有非常明显的协同抗骨髓瘤作用。Sirt1抑制可以部分阻断Hh通路，并在体外和体内赋予硼替佐米敏感性。值得注意的是，SIRT1水平升高也是耐药骨髓瘤细胞的显著标志，这种表达模式在骨髓瘤患者中得到证实，但与RAS/RAF突变无关。在临床上，完全缓解患者的SIRT1表达被抑制，而复发患者的SIRT1表达升高，回顾性分析显示SIRT1表达较高的患者预后较差。综上所述，SIRT1和Hh的协同作用是骨髓瘤耐药的重要机制，联合使用SIRT1抑制剂的治疗方法会使骨髓瘤细胞对蛋白酶体抑制剂敏感。
Multiple myeloma (MM) is still incurable despite the successful application of proteasome inhibitors in clinic. Bortezomib represents the most common chemotherapy for MM, whereas acquired drug resistance and eventually developed relapse remain the major obstruction. In the current study, we established bortezomib-resistant myeloma cell lines and screened gene expression profiles using single cell RNA-sequencing. Resistant MM cells exhibited increased clonogenic potential, specific metabolic, and epigenetic signatures, along with the self-renewal signaling characteristic of MM stem-like cells. Aberrant activation of hedgehog (Hh) signaling was correlated with drug resistance and stem cell-like transcriptional program. The key transcriptional factor GLI2 of the Hh pathway was restricted in the high acetylation and low ubiquitination states in bortezomib-resistant myeloma cells. Further investigation revealed that SIRT1 deacetylates and stabilizes GLI2 protein at lysine 757 and consequentially activates the Hh signaling, and itself serves as a direct target of Hh signaling to format a positive regulating loop. Using combination screening with an epigenetic compound library, we identified the SIRT1 specific inhibitor S1541 and S2804 had very obvious synergetic antimyeloma effect. Sirt1 inhibition could partially impeded the Hh pathway and conferred bortezomib sensitivity in vitro and in vivo. Notably, elevated SIRT1 level was also a prominent hallmark for the resistant myeloma cells, and this expression pattern was confirmed in myeloma patients, but independent of RAS/RAF mutations. Clinically, SIRT1 expression in patients with complete response was suppressed but elevated in relapsed patients, and retrospective analysis showed patients with higher SIRT1 expression had poorer outcomes. In conclusion, the cooperation of SIRT1 and Hh is an important mechanism of drug resistance in myeloma, and therapeutics combining SIRT1 inhibitors will sensitize myeloma cells to proteasome inhibitors.