Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

  • Nat Commun. 2020 Jan 20;11(1):384. doi: 10.1038/s41467-019-14184-0.
Ritika Tiwari   #  1 ,  Nishat Manzar   #  1 ,  Vipul Bhatia  1 ,  Anjali Yadav  1 ,  Mushtaq A Nengroo  2 ,  Dipak Datta  2 ,  Shannon Carskadon  3 ,  Nilesh Gupta  4 ,  Michael Sigouros  5 ,  Francesca Khani  6 ,  Matti Poutanen  7 ,  Amina Zoubeidi  8 ,  Himisha Beltran  9 ,  Nallasivam Palanisamy  3 ,  Bushra Ateeq  10
Affiliations
  • 1. Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India.
  • 2. Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India.
  • 3. Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA.
  • 4. Department of Pathology, Henry Ford Health System, Detroit, MI, 48202, USA.
  • 5. Division of Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 6. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 7. Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland.
  • 8. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
  • 9. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
  • 10. Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India. [email protected].
  • # Contributed equally.
PMID: 31959826 DOI: 10.1038/s41467-019-14184-0
Abstract

Emergence of an aggressive Androgen Receptor (AR)-independent neuroendocrine prostate Cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate Cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for Adjuvant therapies.

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