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

Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Mushtaq A. Nengroo, Dipak Datta, Shannon Carskadon, Nilesh Gupta, Michael Sigouros, Francesca Khani, Matti Poutanen, Amina Zoubeidi, Himisha Beltran, Nallasivam Palanisamy and Bushra Ateeq ()
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Ritika Tiwari: Indian Institute of Technology Kanpur
Nishat Manzar: Indian Institute of Technology Kanpur
Vipul Bhatia: Indian Institute of Technology Kanpur
Anjali Yadav: Indian Institute of Technology Kanpur
Mushtaq A. Nengroo: CSIR-Central Drug Research Institute
Dipak Datta: CSIR-Central Drug Research Institute
Shannon Carskadon: Henry Ford Health System
Nilesh Gupta: Henry Ford Health System
Michael Sigouros: Weill Cornell Medicine
Francesca Khani: Weill Cornell Medicine
Matti Poutanen: University of Turku
Amina Zoubeidi: University of British Columbia
Himisha Beltran: Harvard Medical School
Nallasivam Palanisamy: Henry Ford Health System
Bushra Ateeq: Indian Institute of Technology Kanpur

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14184-0

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