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  • American Association for Cancer Research (AACR)  (3)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 23_Supplement_2 ( 2022-12-01), p. PR005-PR005
    Abstract: Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous, multidomain-containing histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at the enhancers that regulate NB master transcription factors, and drives rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. In parallel, we demonstrate that EP300 and CBP have subdomain-specific functions, with enriched activity for individual domains in distinct tumor lineages. These data provide a foundation for interrogation of these histone acetyltransferases in distinct tumor types and new strategies for therapeutic disruption of subdomain and scaffolding activities of these multidomain proteins in cancer. Citation Format: Adam D. Durbin, Noha Shendy, Audrey Mercier, Yang Zhang, Melissa J. Bikowitz, Logan H. Sigua, Sarah Robinson, Tingjian Wang, Barbara Jonchere, A. Thomas Look, Mark W. Zimmerman, Martine Roussel, Brian J. Abraham, Ernst Schonbrunn, Kimberly Stegmaier, Jun Qi. Targeting EP300 and CBP for therapeutic benefit in pediatric solid tumors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR005.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 410466-3
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB193-LB193
    Abstract: Multiple myeloma (MM) is a malignant plasma cell disorder accounting for 10% of hematologic malignancies. Although high dose chemotherapy and targeted agents have improved patient outcomes, MM remains an incurable disorder. Thus, there is an urgent need to develop novel therapeutic strategies. We discovered that the distinct lysine demethylase 5A (KDM5A) plays a critical role in MM cell growth, through a unique link to MYC-driven transcriptional programs. KDM5A is a dominant regulator of histone H3K4 trimethylation, a histone mark associated with activated gene transcription. We identify that KDM5A interacts with P-TEFb complex and cooperates with MYC to control MYC targeted genes in MM cells. We develop a novel, cell-permeable and selective KDM5 inhibitor, JQKD82 that increases histone H3K4me3, and inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Utilizing genetic ablation together with our inhibitor, we established a detail mechanism that KDM5A is required for transcriptional pause release by P-TEFb at MYC target genes. These data identify KDM5A as a unique vulnerability in MM through regulation of the driving MYC oncogene in MM, and defined JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM. Citation Format: Jun Qi, hiroto Ohguchi, Paul MC Park, tingjian wang, Kenneth C. Anderson, Teru Hideshima, Catrine Johansson, Udo Oppermann, Adam D. Durbin, Berkley Gryder, Javed Khan, xiaofeng zhang. Lysine demethylase 5A is required for MYC driven transcription in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB193.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 4 ( 2021-07-01), p. 370-387
    Abstract: Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3 lysine 4 trimethy­lation (H3K4me3), a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC-targeted genes in multiple myeloma cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself by supporting TFIIH (CDK7)- and P-TEFb (CDK9)–mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in multiple myeloma functioning through regulation of MYC target gene transcription and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for multiple myeloma. Significance: We delineate the function of KDM5A in activating the MYC-driven transcriptional landscape. We develop a cell-permeable KDM5 inhibitor to define the activating role of KDM5A on MYC target gene expression and implicate the therapeutic potential of this compound in mouse models and multiple myeloma patient samples. See related video from the AACR Annual Meeting 2021: https://vimeo.com/554896826
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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