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TRIM28 promotes luminal cell plasticity in a mouse model of prostate cancer

Oncogene volume 42, pages 1347–1359 (2023)Cite this article

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Abstract

The Tripartite motif-containing 28 (TRIM28) transcriptional cofactor is significantly upregulated in high-grade and metastatic prostate cancers. To study the role of TRIM28 in prostate cancer progression in vivo, we generated a genetically-engineered mouse model, combining prostate-specific inactivation of Trp53, Pten and Trim28. Trim28 inactivated NPp53T mice developed an inflammatory response and necrosis in prostate lumens. By conducting single-cell RNA sequencing, we found that NPp53T prostates had fewer luminal cells resembling proximal luminal lineage cells, which are cells with progenitor activity enriched in proximal prostates and prostate invagination tips in wild-type mice with analogous populations in human prostates. However, despite increased apoptosis and reduction of cells expressing proximal luminal cell markers, we found that NPp53T mouse prostates evolved and progressed to invasive prostate carcinoma with a shortened overall survival. Altogether, our findings suggest that TRIM28 promotes expression of proximal luminal cell markers in prostate tumor cells and provides insights into TRIM28 function in prostate tumor plasticity.

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Fig. 1: Trim28 inhibition in the NPp53 mouse model of prostate cancer promotes inflammation and apoptosis.
Fig. 2: Single-cell RNA sequencing of NPp53 and NPp53T prostates suggests TRIM28 is required in proximal luminal phenotype cells.
Fig. 3: Trim28 promotes transdifferentiation to a proximal luminal phenotype.
Fig. 4: Trim28 inhibition in NPp53 prostates reduces overall survival.
Fig. 5: Long-term Trim28 inhibition promotes a pro-tumorigenic immune microenvironment.
Fig. 6: Trim28 inhibition in the castrated NPp53 mouse model produces a phenotype similar to intact mice.

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Data availability

Expression data from single-cell RNA sequencing have been deposited in GEO under accession number GEO: GSE199015.

Material availability

All unique reagents generated in the study are available from the lead contact with a completed material transfer agreement.

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Acknowledgements

We thank Shibata lab members and Kate Chiappinelli for comments on the paper, Michael Shen for mice, Chuan-Yuan Li for plasmids, Hunain Khawaja for assistance with animal breeding and colony maintenance, Gregory Cresswell and the GW Flow Cytometry Core, Keith Crandall, Caitlin Loeffler and the GW Genomics Core, the GW Nanofabrication and Imaging Center, the McCormick Genomic & Proteomic Center and the GW SMHS Writing Institute. This work was supported by the National Institutes of Health NCI grant R00CA194287 to MS.

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Author notes

  1. Ashutosh S. Yende

    Present address: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

  2. Andrew Pletcher

    Present address: Temple University, Philadelphia, PA, USA

  3. Helen Ibeawuchi

    Present address: Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY, USA

  4. These authors contributed equally: Ashutosh S. Yende, Emily C. Williams.

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Ashutosh S. Yende, Emily C. Williams, Andrew Pletcher, Alexandra Helfand, Helen Ibeawuchi, Tanya M. North & Maho Shibata

  2. The George Washington University Cancer Center, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Ashutosh S. Yende, Emily C. Williams, Andrew Pletcher, Alexandra Helfand, Helen Ibeawuchi, Tanya M. North, Patricia S. Latham, Anelia Horvath & Maho Shibata

  3. Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Helen Ibeawuchi & Anelia Horvath

  4. Departments of Pathology and Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Patricia S. Latham

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Contributions

Investigation, ASY, ECW, AP, AHelfand, TMN, MS; Single-cell RNA sequencing analysis, HI, AHorvath, MS; pathology analysis, PSL; writing—original draft, ASY, ECW, MS; writing—review and editing, all authors; conceptualization, funding acquisition, supervision, MS.

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Correspondence to Maho Shibata.

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Yende, A.S., Williams, E.C., Pletcher, A. et al. TRIM28 promotes luminal cell plasticity in a mouse model of prostate cancer. Oncogene 42, 1347–1359 (2023). https://doi.org/10.1038/s41388-023-02655-0

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