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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.
Zhang, Yuxiang; Remillard, David; Onubogu, Ugoma; Karakyriakou, Barbara; Asiaban, Joshua N; Ramos, Anissa R; Bowland, Kirsten; Bishop, Timothy R; Barta, Paige A; Nance, Stephanie; Durbin, Adam D; Ott, Christopher J; Janiszewska, Michalina; Cravatt, Benjamin F; Erb, Michael A.
Afiliación
  • Zhang Y; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Remillard D; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Onubogu U; Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
  • Karakyriakou B; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
  • Asiaban JN; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Ramos AR; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Bowland K; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Bishop TR; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Barta PA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Nance S; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Durbin AD; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Ott CJ; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
  • Janiszewska M; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Cravatt BF; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • Erb MA; Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
Nat Struct Mol Biol ; 30(8): 1160-1171, 2023 08.
Article en En | MEDLINE | ID: mdl-37488358
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mieloma Múltiple / Neuroblastoma Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mieloma Múltiple / Neuroblastoma Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos