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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.

Yuxiang Zhang1, David Remillard1, Ugoma Onubogu2

  • 1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Nature Structural & Molecular Biology
|July 24, 2023
PubMed
Summary
This summary is machine-generated.

Histone deacetylase 1 (HDAC1) and HDAC2 paralogs exhibit synthetic lethality, offering a therapeutic window. Targeting HDAC2 in HDAC1-deficient cancers like neuroblastoma suppresses tumor growth by degrading the NuRD complex.

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Area of Science:

  • Cancer Biology
  • Epigenetics
  • Molecular Oncology

Background:

  • Transcriptional co-regulators are pursued as cancer drug targets, but essential proteins limit therapeutic options.
  • Histone deacetylase 1 (HDAC1) and HDAC2 are crucial for gene regulation and cell survival.
  • Recurrent chromosomal deletions in cancers create vulnerabilities in essential gene pathways.

Purpose of the Study:

  • To identify and characterize a synthetic lethality interaction between HDAC1 and HDAC2 paralogs.
  • To explore the therapeutic potential of targeting this HDAC1/2 synthetic lethality in cancer.
  • To elucidate the molecular mechanisms underlying HDAC1/2 synthetic lethality and its impact on cancer dependencies.

Main Methods:

  • Genetic interaction analysis to identify synthetic lethality between HDAC1 and HDAC2.
  • Utilizing genetic disruption and dTAG-mediated protein degradation to target HDAC2.
  • Investigating the effects of HDAC2 targeting on the nucleosome remodeling and deacetylase (NuRD) complex and chromatin accessibility.
  • Analyzing cancer dependencies in neuroblastoma and multiple myeloma.

Main Results:

  • HDAC1 and HDAC2 exhibit collateral synthetic lethality, where hemizygous deletion of one paralog is lethal with the deletion of the other.
  • Targeting HDAC2 in HDAC1-deficient neuroblastoma suppressed tumor growth in vitro and in vivo.
  • Degradation of HDAC2 led to the degradation of NuRD complex members, reduced chromatin accessibility, and impaired transcription.
  • NuRD complex subunits were identified as dependencies in neuroblastoma and multiple myeloma.

Conclusions:

  • HDAC1/2 collateral synthetic lethality presents a novel therapeutic target for cancers with specific chromosomal deletions.
  • Targeted degradation of HDAC2 offers a strategy to exploit this synthetic lethality and impact NuRD-associated cancer dependencies.
  • Development of paralog-selective HDAC1 or HDAC2 degraders could leverage this vulnerability for cancer treatment.