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

Mar 19, 2019

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 It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature