A1 Refereed original research article in a scientific journal
Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer
Authors: Tiwari R, Manzar N, Bhatia V, Yadav A, Nengroo MA, Datta D, Carskadon S, Gupta N, Sigouros M, Khani F, Poutanen M, Zoubeidi A, Beltran H, Palanisamy N, Ateeq B
Publisher: NATURE PUBLISHING GROUP
Publication year: 2020
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: 384
Volume: 11
Issue: 1
Number of pages: 19
ISSN: 2041-1723
eISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-019-14184-0
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/46061820
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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