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The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity

Lin He1, Chunyu Yu2, Sen Qin3

  • 1Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.

Molecular Cell
|November 7, 2023
PubMed

Insights

PSMD14, a proteasome component, regulates myeloma by interacting with NSD2 and controlling gene expression. Inhibiting PSMD14 enhances bortezomib treatment and improves survival in myeloma patients.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Oncology

Background:

  • 19S proteasome regulatory particle (RP) inhibition shows promise for bortezomib-resistant myeloma.
  • The precise role of PSMD14, a 19S RP component, in myeloma pathogenesis beyond proteasomal inhibition is unclear.

Purpose of the Study:

  • To elucidate the non-proteasomal function of PSMD14 in myeloma.
  • To investigate the interaction of PSMD14 with other proteins and its role in gene regulation.
  • To evaluate PSMD14 as a therapeutic target for myeloma.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to assess protein-DNA interactions.
  • Histone modification assays to evaluate deubiquitinase activity.
  • Genomic and epigenomic analyses to identify target genes.
  • In vitro and in vivo studies to assess drug synergy.

Main Results:

  • PSMD14 interacts with NSD2 on chromatin, independent of the 19S RP.
  • PSMD14 functions as a histone H2AK119 deubiquitinase, promoting H3K36 dimethylation.
  • A PSMD14/NSD2-RELA positive feedback loop drives myelomagenesis.
  • PSMD14 inhibitors synergize with bortezomib, enhancing anti-myeloma activity.
  • Elevated PSMD14 expression correlates with poor survival in myeloma patients.

Conclusions:

  • PSMD14 is an epigenetic regulator and a driver of myeloma.
  • Targeting PSMD14 offers a novel strategy to overcome bortezomib resistance in myeloma.
  • PSMD14 represents a promising therapeutic target for myeloma treatment.
Keywords:
19S regulatory particle26S proteasomeNSD2PSMD14RELAbortezomib resistancehistone methylationhistone ubiquitinationmultiple myelomat(4;14) translocation

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