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

Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Shannon Carskadon, Nilesh Gupta, Amina Zoubeidi, Nallasivam Palanisamy, Bushra Ateeq

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Mar 19, 2019
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Received Date: 7th March 19

The SPINK1 overexpression represents ~10-25% of prostate cancer (PCa) patients associated with overall poor-prognosis. Androgen-deprivation therapy (ADT) remains mainstay for PCa treatment, however, majority of these patients eventually progress to castration-resistant stage. Despite adverse-effects of ADT, the role of androgen receptor (AR) signaling in SPINK1-mediated oncogenesis remains unexplored. Here, we show that AR and its corepressor, REST, function as transcriptional-repressor of SPINK1, while androgen-deprivation relieves this repression leading to SPINK1 upregulation. Concurringly, an inverse-association between SPINK1 and AR expression was observed across multiple PCa cohorts. Moreover, lineage-reprogramming factor SOX2 in-turn binds to SPINK1 promoter leading to its transactivation. Conversely, Casein Kinase-1 inhibitor stabilizes the REST levels, which cooperates with AR and conjures SPINK1 transcriptional-repression, thus impeding SPINK1-mediated oncogenesis. Additionally, SPINK1 elicits epithelial-mesenchymal-transition, drug-resistance, stemness and cellular-plasticity. Collectively, our findings provide a plausible explanation to the paradoxical clinical-outcomes of ADT, possibly due to increased SPINK1 levels, and offers strategy for adjuvant-therapies.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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