4.5 Article

Deubiquitinating enzyme inhibitor alleviates cyclin A1-mediated proteasome inhibitor tolerance in mixed-lineage leukemia

期刊

CANCER SCIENCE
卷 112, 期 6, 页码 2287-2298

出版社

WILEY
DOI: 10.1111/cas.14892

关键词

cyclin A1; deubiquitinating enzyme inhibitor; drug tolerance; mixed‐ linage leukemia; proteasome inhibitor

类别

资金

  1. National Key Research and Development Program of China [2018YFA0107802]
  2. National Natural Science Foundation of China [81973996]
  3. Postdoctoral Science Foundation of China [2020M681338, 2020M681339]
  4. Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant [20161304]
  5. Program of Shanghai Academic/Technology Research Leader [19XD1402500]
  6. Shanghai Municipal Health Commission [2019CXJQ01]
  7. Collaborative Innovation Center of Hematology

向作者/读者索取更多资源

Drug resistance is a major challenge in cancer treatment, and regulating cyclin A1 to alter reversible cell cycle dynamics can promote the development of PI tolerance. Combination therapy with PI and DUB inhibitors can overcome this drug resistance.
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.

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