WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97/VCP axis

Synthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics re...

Full description

Saved in:

Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; pp. 6059 - 17
Main Authors:	Rodríguez Pérez, Fernando, Natwick, Dean, Schiff, Lauren, McSwiggen, David, Heckert, Alec, Huey, Melina, Morrison, Huntly, Loo, Mandy, Miranda, Rafael G., Filbin, John, Ortega, Jose, Van Buren, Kayla, Murnock, Danny, Tao, Arnold, Butler, Renee, Cheng, Kylie, Tarvestad, William, Zhang, Zhengjian, Gonzalez, Eric, Miller, Rand M., Kelly, Marcus, Tang, Yangzhong, Ho, Jaclyn, Anderson, Daniel, Bashore, Charlene, Basham, Stephen
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-07-2024 Nature Publishing Group Nature Portfolio
Subjects:	14 14/1 14/19 14/34 49 631/337/458/582 631/92/609 82/80 82/83 96/95 Animals Biocompatibility Cancer Cancer therapies Cell Line, Tumor Chromatin Chromatin - metabolism Degradation DNA helicase Drug development Female Humanities and Social Sciences Humans In vivo methods and tests Lethality Mice Microsatellite Instability multidisciplinary Nuclear Proteins - genetics Nuclear Proteins - metabolism Optics Proteasomes Protein Inhibitors of Activated STAT - genetics Protein Inhibitors of Activated STAT - metabolism Proteolysis - drug effects Regulatory mechanisms (biology) Science Science (multidisciplinary) SUMO protein Sumoylation - drug effects Tracking Transcription Factors - genetics Transcription Factors - metabolism Valosin Containing Protein - genetics Valosin Containing Protein - metabolism Werner Syndrome Helicase - genetics Werner Syndrome Helicase - metabolism Xenograft Model Antitumor Assays Xenotransplantation
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Synthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics remain poorly understood. Here, we used single-molecule tracking (SMT) in combination with a WRN inhibitor to examine WRN dynamics within the nuclei of living cancer cells. WRN inhibition traps the helicase on chromatin, requiring p97/VCP for extraction and proteasomal degradation in a MSI-H dependent manner. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation. Finally, we show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells and confirm the in vivo activity of WRN inhibition using an MSI-H mouse xenograft model. This work elucidates a regulatory mechanism for WRN that may facilitate identification of new therapeutic modalities, and highlights the use of SMT as a tool for drug discovery and mechanism-of-action studies. New optical methods for investigating the activity of small molecules in cells may facilitate development of anticancer therapeutics. Here, the authors use a super-resolution optical platform and single molecule tracking to gain insight into WRN regulation in cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-50178-3