Nat Commun. 2020 Jan 20;11(1):384. doi: 10.1038/s41467-019-14184-0.
Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer.
Tiwari R1, Manzar N1, Bhatia V1, Yadav A1, Nengroo MA2, Datta D2, Carskadon S3, Gupta N4, Sigouros M5, Khani F6, Poutanen M7, Zoubeidi A8, Beltran H9, Palanisamy N3, Ateeq B10.
Author information
- 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. bushra@iitk.ac.in.
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.
- PMID:
- 31959826
- DOI:
- 10.1038/s41467-019-14184-0
