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Article: Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

bioRxiv : the preprint server for biology

2024

Abstract: The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors ( ... ...

Abstract	The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.26.550648
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

eLife

2024 Volume 12

Abstract: The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors ( ... ...

Abstract	The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.
MeSH term(s)	Humans ; Antineoplastic Agents/pharmacology ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/genetics ; Cell Line, Tumor ; Histone-Lysine N-Methyltransferase/metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Myeloid-Lymphoid Leukemia Protein/genetics ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Ribosomes/drug effects ; Ribosomes/metabolism ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Protein p53/genetics ; Peptidomimetics/pharmacology
Chemical Substances	Antineoplastic Agents ; Cell Cycle Proteins ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Intracellular Signaling Peptides and Proteins ; KMT2A protein, human ; MDM4 protein, human ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Nuclear Proteins ; Proto-Oncogene Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; WDR5 protein, human ; Peptidomimetics
Language	English
Publishing date	2024-04-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.90683
Database	MEDical Literature Analysis and Retrieval System OnLINE

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