Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Sci. 2021 Jun;112(6):2287-2298. doi: 10.1111/cas.14892. Epub 2021 Apr 5.
Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell-cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1-engaged cell-cycle regulation in PI resistance in MLL cells, and suggest that cell-cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.
耐药性是癌症治疗的重大障碍。耐药性是由最初可逆的耐药物癌细胞发展而来的，这为阻止癌症复发提供了治疗机会。人们已经深入研究了针对蛋白酶体抑制剂（PI）治疗的耐药机制，但耐药物癌细胞如何协调其对药物挑战的适应性反应仍然很大程度上未知。在这里，我们证明了细胞周期蛋白 A1 的抑制可在混合谱系白血病（MLL）细胞中引发短暂的 PI 耐受。这种适应性过程涉及细胞周期蛋白 A1 的可逆下调，通过细胞周期停滞促进 PI 耐药性。PI 耐受的 MLL 细胞获得了对 cyclin A1 的依赖性，该依赖性受 MLL 蛋白的直接调节。cyclin A1 功能丧失导致药物耐受出现，这与患者复发和生存减少有关。PI 和去泛素化酶（DUB）抑制剂的联合治疗通过染色质间的组蛋白 H2B 单泛素化和 MLL 介导的组蛋白 H3 赖氨酸 4 甲基化之间的染色质串扰，恢复 cyclin A1 的表达，从而克服了这种耐药性。这些结果揭示了 cyclin A1 参与的细胞周期调节在 MLL 细胞中的 PI 耐药性中的重要性，并表明 DUB 抑制剂通过细胞周期再进入可能代表一种有前途的表观遗传治疗策略，以防止获得性药物耐药性。
