The cooperation among the core regulatory circuitry transcription factors and MYCN on DNA binding [HAND2-MYCN-CRC-knockdown_ChIPseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184057 | GEO | 2023/03/29
REPOSITORIES: GEO
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Project description:HAND2 assists MYCN bind to DNA.
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Project description:A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.
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Project description:A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.
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Project description:A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.
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Project description:A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.
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Project description:Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting drugging transcription as a means to advance the treatment of high risk neuroblastoma.
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Project description:Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting Òdrugging transcriptionÓ as a means to advance the treatment of high risk neuroblastoma.
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Project description:Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting Òdrugging transcriptionÓ as a means to advance the treatment of high risk neuroblastoma.
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Project description:In this study we identified genes regulated by HAND2 or MYCN or both MYCN and HAND2 in IMR32 cells.
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