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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities
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Journal Article
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities
2023
Overview
Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (
HDAC1
) and
HDAC2
, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of
HDAC1
-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2–NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify
HDAC1
/
2
collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.
Here, the authors show that HDAC1 and HDAC2 genetically interact, with each paralog being synthetically lethal with hemizygous deletion of the other. Mechanistically, HDAC1/2 co-deficiency leads to degradation of the NuRD complex, decreased chromatin accessibility and aberrant enhancer-based interactions.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 631/67
/ 631/92
/ Biomedical and Life Sciences
/ Cancer
/ Genomes
/ Histone Deacetylase 1 - genetics
/ Histone Deacetylase 1 - metabolism
/ Histone Deacetylase 2 - genetics
/ Histone Deacetylase 2 - metabolism
/ Humans
/ Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics
/ Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism
