Tiwari, Ritika ; Manzar, Nishat ; Bhatia, Vipul ; Yadav, Anjali ; Nengroo, Mushtaq A. ; Datta, Dipak ; Carskadon, Shannon ; Gupta, Nilesh ; Sigouros, Michael ; Khani, Francesca ; Poutanen, Matti ; Zoubeidi, Amina ; Beltran, Himisha ; Palanisamy, Nallasivam ; Ateeq, Bushra (2020) Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer Nature Communications, 11 (1). ISSN 2041-1723
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Official URL: http://doi.org/10.1038/s41467-019-14184-0
Related URL: http://dx.doi.org/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.
Item Type: | Article |
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Source: | Copyright of this article belongs to Springer Nature Limited |
ID Code: | 127228 |
Deposited On: | 13 Oct 2022 09:17 |
Last Modified: | 13 Oct 2022 09:17 |
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