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.

对蛋白酶体抑制剂的获得性化学耐药性是治疗多发性骨髓瘤的主要障碍，但关键的监管机构和潜在机制仍有待探索。我们发现，使用基于 SILAC 的乙酰蛋白质组学测定，高水平的 HP1γ 与耐硼替佐米的骨髓瘤细胞中的低乙酰化修饰相关，并且较高的 HP1γ 水平与较差的临床结果呈正相关。从机制上讲，硼替佐米耐药骨髓瘤细胞中升高的 HDAC1 使赖氨酸 5 处的 HP1γ 去乙酰化，从而减轻泛素介导的蛋白质降解以及异常的 DNA 修复能力。HP1γ 与 MDC1 相互作用以诱导 DNA 修复，CD40、果寡糖和JUN。因此，通过使用 HDAC1 抑制剂靶向 HP1γ 稳定性可使硼替佐米耐药的骨髓瘤细胞在体外和体内对蛋白酶体抑制剂治疗重新敏感。我们的研究结果阐明了 HP1γ 在诱导对骨髓瘤细胞蛋白酶体抑制剂的耐药性方面的先前未被认识的作用，并表明靶向 HP1γ 可能有效克服难治性或复发性多发性骨髓瘤患者的耐药性。