Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance.
Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance.
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去乙酰化诱导的HP1γ核凝聚促进多发性骨髓瘤耐药性
DOI：
10.1038/s41467-023-37013-x
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发表时间：
2023-03-09
影响因子：
16.6
通讯作者：
Liu, Zhiqiang
中科院分区：
文献类型：
--
作者：
Li, Xin;Wang, Sheng;Xie, Ying;Jiang, Hongmei;Guo, Jing;Wang, Yixuan;Peng, Ziyi;Hu, Meilin;Wang, Mengqi;Wang, Jingya;Li, Qian;Wang, Yafei;Liu, Zhiqiang
对蛋白酶体抑制剂的获得性耐药是治疗多发性骨髓瘤的主要障碍，但关键调控因子和潜在机制仍有待探索。我们使用基于SILAC的乙酰蛋白质组学分析发现，在硼替佐米耐药的骨髓瘤细胞中，高水平的HP 1 γ与低乙酰化修饰相关，并且较高的HP 1 γ水平与临床预后较差呈正相关。从机制上讲，硼替佐米耐药骨髓瘤细胞中HDAC1的升高使HP1γ在赖氨酸5处脱乙酰化，从而使泛素介导的蛋白质降解以及异常的DNA修复能力减弱。HP 1 γ与MDC 1相互作用诱导DNA修复，同时HP 1 γ的去乙酰化修饰和与MDC 1的相互作用增强了HP 1 γ蛋白的核凝聚及其对蛋白酶体抑制剂如CD 40、FOS和JUN敏感性的靶基因的染色质可及性。通过使用HDAC 1抑制剂靶向HP 1 γ稳定性，在体外和体内使硼替佐米耐药骨髓瘤细胞对蛋白酶体抑制剂治疗重新敏感。我们的发现阐明了以前未被认识到的HP1γ在诱导骨髓瘤细胞对蛋白酶体抑制剂的耐药性中的作用，并表明靶向HP1γ可能有效地克服难治性或复发性多发性骨髓瘤患者的耐药性。多发性骨髓瘤（MM）对蛋白酶体抑制剂（PI）获得性耐药的分子机制仍有待探讨。在这里，作者强调了异染色质蛋白1 γ作为克服MM对PI耐药性的潜在靶点的作用。
Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients. The molecular mechanisms underlying acquired chemoresistance to proteasome inhibitors (PIs) in multiple myeloma (MM) remain to be explored. Here, the authors highlight the role of heterochromatin protein 1 gamma as a potential target for overcoming resistance to PIs in MM.
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