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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.
Abstract:
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.
Insights
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.
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.
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