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

Publication ,  Journal Article
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 ...
Published in: Mol Ther
January 5, 2022

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.

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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

January 5, 2022

Volume

30

Issue

1

Start / End Page

485 / 500

Location

United States

Related Subject Headings

  • Signal Transduction
  • Serine-Threonine Kinase 3
  • Serine
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Male
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • Cell Line, Tumor
  • Biotechnology
 

Citation

APA
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ICMJE
MLA
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Schirmer, A. U., Driver, L. M., Zhao, M. T., Wells, C. I., Pickett, J. E., O’Bryne, S. N., … Macias, E. (2022). Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther, 30(1), 485–500. https://doi.org/10.1016/j.ymthe.2021.08.029
Schirmer, Amelia U., Lucy M. Driver, Megan T. Zhao, Carrow I. Wells, Julie E. Pickett, Sean N. O’Bryne, Benjamin J. Eduful, et al. “Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.Mol Ther 30, no. 1 (January 5, 2022): 485–500. https://doi.org/10.1016/j.ymthe.2021.08.029.
Schirmer AU, Driver LM, Zhao MT, Wells CI, Pickett JE, O’Bryne SN, et al. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2022 Jan 5;30(1):485–500.
Schirmer, Amelia U., et al. “Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.Mol Ther, vol. 30, no. 1, Jan. 2022, pp. 485–500. Pubmed, doi: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 J-T, Drewry DH, Macias E. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2022 Jan 5;30(1):485–500.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

January 5, 2022

Volume

30

Issue

1

Start / End Page

485 / 500

Location

United States

Related Subject Headings

  • Signal Transduction
  • Serine-Threonine Kinase 3
  • Serine
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Male
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • Cell Line, Tumor
  • Biotechnology