ArticleNature structural & molecular biology2023
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.
Article in Nature structural & molecular biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- Inhibition of USP7 Destabilizes the Noncanonical PRC1.1 Complex and Induces Neuroblastoma Differentiation.Molecular cancer research : MCR · 2026Article
- Epigenetic and chromatin remodeling mechanisms across cardiomyopathies: a comprehensive review.Epigenetics & chromatin · 2026Review
- Disruption of the SAGA CORE triggers collateral degradation of KAT2A.Nature communications · 2026Article
- CHD4 epigenetically coordinates genomic instability and immunosuppression to drive pan-cancer progression and confer HDAC inhibitor sensitivity.Clinical and experimental medicine · 2026Article
- Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition.Communications biology · 2026Article
- Chemical Perturbations Impacting Histone Acetylation Govern Colorectal Cancer Differentiation.Gastroenterology · 2026Article
- HDAC2-mediated chromatin remodeling drives hepatocellular carcinoma progression: an integrative analysis of computational pathology and multi-transcriptomics.Journal of translational medicine · 2025Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Akkermansia muciniphila-Derived N-Acetylspermidine Modulates the Localization of Intestinal α1,2-Fucosylated Proteins to Maintain Gut Homeostasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- CoREST in pieces: Dismantling the CoREST complex for cancer therapy and beyond.Science advances · 2025Review
- High-throughput transcriptome analysis reveals a developmental increase in Acvr1c which mediates epigenetic repression of the gene encoding the pubertal brake, Makorin ring finger protein 3.NAR molecular medicine · 2025Article
- Lineage-Selective Dependencies in Pediatric Cancers.Cold Spring Harbor perspectives in medicine · 2025Review
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- Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application.Signal transduction and targeted therapy · 2024Review
- Pharmacological targeting of the cancer epigenome.Nature cancer · 2024Review
- Developmental origins shape the paediatric cancer genome.Nature reviews. Cancer · 2024Review
- Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.Cell reports · 2024Article
- MDM2 Antagonist Idasanutlin Reduces HDAC1/2 Abundance and Corepressor Partners but Not HDAC3.ACS medicinal chemistry letters · 2024Article
- Chemical-genetics refines transcription factor regulatory circuits.Trends in cancer · 2024Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.