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Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
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Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance

Xin Li1, Sheng Wang1, Ying Xie1

  • 1The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases; Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, 300070, China.

Nature Communications
|March 9, 2023
PubMed

Insights

High levels of HP1γ protein promote drug resistance in multiple myeloma by hindering proteasome inhibitor effectiveness. Targeting HP1γ stability with HDAC1 inhibitors can re-sensitize resistant cells, offering a new therapeutic strategy for patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acquired chemoresistance to proteasome inhibitors presents a significant challenge in multiple myeloma treatment.
  • The precise molecular regulators and mechanisms driving this drug resistance are not fully understood.

Purpose of the Study:

  • To investigate the role of HP1γ protein in the development of bortezomib resistance in multiple myeloma.
  • To explore the underlying mechanisms by which HP1γ influences drug sensitivity and identify potential therapeutic targets.

Main Methods:

  • Utilized SILAC-based acetyl-proteomics to compare acetylation patterns in bortezomib-sensitive and resistant myeloma cells.
  • Investigated the interaction between HP1γ, HDAC1, and MDC1, and their impact on DNA repair and gene expression.
  • Assessed the efficacy of targeting HP1γ stability using HDAC1 inhibitors in vitro and in vivo models.

Main Results:

  • Elevated HP1γ levels correlate with reduced acetylation and poorer clinical outcomes in multiple myeloma patients.
  • HDAC1 deacetylates HP1γ, stabilizing the protein and promoting DNA repair and drug resistance.
  • HP1γ deacetylation enhances its interaction with MDC1, leading to increased nuclear condensation and altered chromatin accessibility of key genes.

Conclusions:

  • HP1γ plays a critical, previously unrecognized role in mediating drug resistance to proteasome inhibitors in multiple myeloma.
  • Targeting HP1γ stability through HDAC1 inhibition demonstrates potential for overcoming bortezomib resistance.
  • This strategy offers a promising therapeutic avenue for patients with refractory or relapsed multiple myeloma.

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