Title | Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer. |
Publication Type | Journal Article |
Year of Publication | 2020 |
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 |
Journal | Nat Commun |
Volume | 11 |
Issue | 1 |
Pagination | 384 |
Date Published | 2020 01 20 |
ISSN | 2041-1723 |
Keywords | Androgen Receptor Antagonists, Animals, Casein Kinase I, Cell Line, Tumor, Co-Repressor Proteins, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Male, Mice, Nerve Tissue Proteins, Neuroendocrine Tumors, Prostate, Prostatic Neoplasms, Receptors, Androgen, SOXB1 Transcription Factors, Transcription, Genetic, Trypsin Inhibitor, Kazal Pancreatic, Up-Regulation, Xenograft Model Antitumor Assays |
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. |
DOI | 10.1038/s41467-019-14184-0 |
Alternate Journal | Nat Commun |
PubMed ID | 31959826 |
PubMed Central ID | PMC6971084 |
Related Faculty:
Francesca Khani, M.D.