PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma
In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.
Authors
- Julia Dmytryshyn
- C.H. Arrowsmith (ORCID: https://orcid.org/0000-0002-4971-3250)
- Joseph Walton (ORCID: https://orcid.org/0000-0002-4654-4404)
- Brian Raught (ORCID: https://orcid.org/0000-0001-6145-4776)
- Jalna Meens (ORCID: https://orcid.org/0000-0001-5274-3744)
- Karen Arevalo (ORCID: https://orcid.org/0000-0003-1838-6231)
- Anthony Apostoli
- Panagiotis Prinos (ORCID: https://orcid.org/0000-0001-8785-7856)
- Eric X. Chen (ORCID: https://orcid.org/0000-0002-4581-8848)
- Christina Karamboulas
- Laurie Ailles (ORCID: https://orcid.org/0000-0001-7289-8882)
- Angel Sau Ni Ng
- Jonathan St-Germain
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Princess Margaret Cancer Centre (CA)
- Structural Genomics Consortium (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1038/s41467-024-52507-y
- Citations
- 11
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- Bristol-Myers Squibb
- Pfizer
- Bayer
- Canadian Urological Association
- McGill University
- Genome Canada
- Cancer Research Society
- Princess Margaret Cancer Foundation
- Merck KGaA
- Ontario Institute for Cancer Research
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Government of Ontario
- Ontario Genomics Institute
- Genentech