1. ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.
- Author
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Qian C, Yang Q, Rotinen M, Huang R, Kim H, Gallent B, Yan Y, Cadaneanu RM, Zhang B, Kaochar S, Freedland SJ, Posadas EM, Ellis L, Di Vizio D, Morrissey C, Nelson PS, Brady L, Murali R, Campbell MJ, Yang W, Knudsen BS, Mostaghel EA, Ye H, Garraway IP, You S, and Freeman MR
- Subjects
- Male, Humans, Cell Line, Tumor, Phenylthiohydantoin pharmacology, Phenylthiohydantoin analogs & derivatives, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Epigenesis, Genetic, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors drug therapy, Animals, Cell Lineage genetics, Mice, Receptors, Androgen metabolism, Receptors, Androgen genetics, Adenocarcinoma genetics, Adenocarcinoma pathology, Adenocarcinoma metabolism, Adenocarcinoma drug therapy, Receptors, Glucocorticoid metabolism, Receptors, Glucocorticoid genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, Benzamides pharmacology, Nitriles pharmacology, Gene Expression Regulation, Neoplastic
- Abstract
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2024
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