全反式维甲酸通过IRF1调控OAS1启动子乙酰化克服多发性骨髓瘤对蛋白酶体抑制剂耐药

蛋白酶体抑制剂（PIs）耐药是多发性骨髓瘤（MM）预后不良的主要原因，目前尚无克服PIs耐药的有效策略。我们前期工作发现MM中OAS1基因表达下调及其下游OAS/RNase L通路下调可能是导致MM对PIs耐药的新机制，而OAS1基因启动子去乙酰化可能是导致OAS1基因表达下调的主要原因，但其具体机制有待阐明。我们预实验还发现“高效、低毒、经济”的全反式维甲酸可上调OAS1基因表达，而抑癌基因IRF1可能是ATRA调控OAS1启动子乙酰化的关键分子，然而三者具体调控机制未明。本研究拟在前期工作基础上从分子、细胞、动物和临床水平进一步验证ATRA具有协助克服MM细胞对PIs的耐药的潜能，深入分析ATRA调控IRF1的具体机理，明确IRF1如何通过募集PCAF乙酰化OAS1启动子而影响OAS1参与MM细胞耐药的具体分子机制，为临床治疗提供新策略。

Proteasome inhibitors (PIs) resistance is the leading cause of poor prognosis in multiple myeloma (MM). Our study found that the downregulation of OAS1 gene and its downstream OAS / RNase L pathway might result in MM resistance to PIs, while the deacetylation of OAS1 gene promotor might be the main cause of OAS1 down-regulation, but the underlying mechanism remained to be elucidated. In addition, we also found that all trans retinoic acid with "high efficiency, low toxicity and economic" could upregulate OAS1 gene, while the tumor suppressor gene IRF1 might be the key molecule for ATRA mediated acetylation of OAS1 promoter. However, the underlying regulatory mechanism among ATRA, IRF1 and OAS1 is not yet clear. Based on our previous work, this study aims to further verify ATRA has its potential to help overcome the PIs resistance in MM cells by the molecular, cellular, animal and clinical levels. Meanwhile, this study intends to further explore the specific mechanism of how ATRA regulates IRF1, as well as clarify how IRF1 participates in MM cell resistance by recruiting PCAF and acetylating OAS1 promoter. Our investigation would contribute to reveal the new mechanism of PIs resistance and provide a new strategy for the treatment of PIs-resistant MM patients.