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Schirmer AU, Driver LM, Zhao MT, et al. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2021;30(1):485-500doi: 10.1016/j.ymthe.2021.08.029.
Schirmer, A. U., Driver, L. M., Zhao, M. T., Wells, C. I., Pickett, J. E., O'Bryne, S. N., Eduful, B. J., Yang, X., Howard, L., You, S., Devi, G. R., DiGiovanni, J., Freedland, S. J., Chi, J. T., Drewry, D. H., & Macias, E. (2022). Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Molecular therapy : the journal of the American Society of Gene Therapy, 30(1), 485-500. https://doi.org/10.1016/j.ymthe.2021.08.029
Schirmer, Amelia U, et al. "Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer." Molecular therapy : the journal of the American Society of Gene Therapy vol. 30,1 (2022): 485-500. doi: https://doi.org/10.1016/j.ymthe.2021.08.029
Schirmer AU, Driver LM, Zhao MT, Wells CI, Pickett JE, O'Bryne SN, Eduful BJ, Yang X, Howard L, You S, Devi GR, DiGiovanni J, Freedland SJ, Chi JT, Drewry DH, Macias E. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2022 Jan 05;30(1):485-500. doi: 10.1016/j.ymthe.2021.08.029. Epub 2021 Aug 25. PMID: 34450249.
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Mol Ther. 2022 Jan 05;30(1):485-500. doi: 10.1016/j.ymthe.2021.08.029. Epub 2021 Aug 25.

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

Molecular therapy : the journal of the American Society of Gene Therapy

Amelia U Schirmer, Lucy M Driver, Megan T Zhao, Carrow I Wells, Julie E Pickett, Sean N O'Bryne, Benjamin J Eduful, Xuan Yang, Lauren Howard, Sungyong You, Gayathri R Devi, John DiGiovanni, Stephen J Freedland, Jen-Tsan Chi, David H Drewry, Everardo Macias

Affiliations

  1. Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
  2. Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  3. Duke Cancer Institute Biostatistics Shared Resource, Duke University, Durham, NC 27710, USA.
  4. Department of Biomedical Science and Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  5. Department of Surgery, Duke University School of Medicine, Durham NC 27710, USA.
  6. Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.
  7. Department of Surgery and Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048 and the Durham VA Medical Center, Durham, NC 27705, USA.
  8. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
  9. Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
  10. Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: [email protected].

PMID: 34450249 DOI: 10.1016/j.ymthe.2021.08.029

Abstract

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.

Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Keywords: Hippo tumor suppressor; STK3; kinase inhibitor; non-canonical; prostate cancer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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