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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run]

ABSTRACT: Transcriptional coregulators 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 may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered 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 translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and lymphoid malignancies. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption 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 turnover 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. Several of the degraded NuRD complex subunits are themselves lineage-specific cancer dependencies, providing motivation to develop paralog-selective HDAC degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202703 | GEO | 2022/06/09

REPOSITORIES: GEO

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

Project description:Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption 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. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

2023-06-11 | PXD034444 | Pride

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [ATAC-Seq]

Project description:Transcriptional coregulators 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 may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered 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 translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption 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. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

2022-06-09 | GSE202702 | GEO

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

2022-06-09 | GSE202705 | GEO

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

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

| PRJNA837075 | ENA

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

| PRJNA837077 | ENA

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run]

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run]

| PRJNA837078 | ENA

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [ATAC-Seq]

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [ATAC-Seq]

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Comparative genomic hybridisation of gDNA from HDAC1-/-; HDAC2+/- diseased mouse thymocytes and sample matched wild-type tail

Project description:Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T cell specific deletion and performed comparative genomic hybridisation using genomic DNA from HDAC1-/-; HDAC2+/- diseased thymocytes and sample-matched, wild-type tail. A data set from a related transcription-profiling study comparing HDAC1-/-; HDAC2+/- mouse thymus tissue against thymus tissues from wild-type counterparts has also been deposited at ArrayExpress under accession E-MTAB-1432: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1432

2013-01-08 | E-MTAB-1433 | biostudies-arrayexpress

Expression data for developing a GE-HTS signature for neuroblastoma differentiation

Project description:Gene expression data from BE(2)-C cells treated in triplicate with either vehicle (DMSO), 5 M-NM-<M all-trans retinoic acid (ATRA), 1 mM valproic acid (VPA), or 5 M-NM-<M ATRA + 1 mM VPA for 6, 24, or 72 hours. Genome-wide expression profiling was performed using Affymetrix U133A microarrays. While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective Class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation. BE(2)-C cells were treated in triplicate with either vehicle (DMSO), 5 M-NM-<M all-trans retinoic acid (ATRA), 1 mM valproic acid (VPA), or 5 M-NM-<M ATRA + 1 mM VPA for 6, 24, or 72 hours. Genome-wide expression profiling was performed using Affymetrix U133A microarrays [HT-HG_U133A Early Access].

2013-04-08 | E-GEOD-45587 | biostudies-arrayexpress

Expression data for developing a GE-HTS signature for neuroblastoma differentiation

Project description:Gene expression data from BE(2)-C cells treated in triplicate with either vehicle (DMSO), 5 μM all-trans retinoic acid (ATRA), 1 mM valproic acid (VPA), or 5 μM ATRA + 1 mM VPA for 6, 24, or 72 hours. Genome-wide expression profiling was performed using Affymetrix U133A microarrays. While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective Class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.

2013-04-08 | GSE45587 | GEO

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