Transcriptional Reprogramming in Prostate Cancer: Altered AR Activity, the Modulatory Role of CDK8/19, and Prospects for Combination Therapy
- 1Translational Medicine Research Center, Sirius University of Science and Technology, 1 Olympic Avenue, 354340 Sochi, Russia
- 2Institute of Experimental Oncology and Carcinogenesis, Blokhin National Medical Research Center of Oncology, 24 Kashirskoye Shosse, 115522 Moscow, Russia
Abstract
Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with resistance to androgen-deprivation therapy (ADT) being the major clinical challenge. A key driver of this resistance is transcriptional reprogramming, during which androgen receptor (AR) activity shifts from ligand-dependent signaling to reactivation via splice variants such as AR-V7 and eventually to AR-negative states. The oncogene c-MYC plays a pivotal role through context-dependent crosstalk with AR, suppressing canonical AR-dependent transcription while promoting its own oncogenic program. This reprogramming is sustained by dysregulation of RB1/E2F, NF-κB, PI3K/AKT/mTOR, WNT/β-catenin, and Hippo/YAP/TAZ pathways, alongside N-MYC and L-MYC activation, forming an interconnected network driving phenotypic plasticity. This review focuses on cyclin-dependent kinases 8 and 19 (CDK8/19), components of the Mediator complex kinase module, as potential regulators of epigenetic plasticity in PCa capable of modulating both AR-dependent and AR-independent transcription. Preclinical studies show that CDK8/19 inhibition suppresses castration-resistant prostate cancer (CRPC) xenograft growth, restores ADT sensitivity, and additively enhances enzalutamide even in AR-V7-expressing resistant models, though the mechanisms of CDK8/19-mediated AR regulation remain largely undefined. We analyze the signaling pathways driving AR activity changes during PCa progression, evaluate potential mechanisms of CDK8/19-mediated AR regulation, and assess the therapeutic potential of CDK8/19 inhibitors with ADT.
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BibTeX
@article{dodina2026transcriptional,
title = {{Transcriptional Reprogramming in Prostate Cancer: Altered AR Activity, the Modulatory Role of CDK8/19, and Prospects for Combination Therapy}},
author = {Maria Dodina and Polina Pavlova and Polina Kuzkokova and Aleksey Krasnyi and Alexander Shtil and Roman Ivanov and Ekaterina Minskaia},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219855},
url = {https://www.mdpi.com/1422-0067/27/21/9855},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Transcriptional Reprogramming in Prostate Cancer: Altered AR Activity, the Modulatory Role of CDK8/19, and Prospects for Combination Therapy
AU - Maria Dodina
AU - Polina Pavlova
AU - Polina Kuzkokova
AU - Aleksey Krasnyi
AU - Alexander Shtil
AU - Roman Ivanov
AU - Ekaterina Minskaia
PY - 2026
DA - 2026/11/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219855
UR - https://www.mdpi.com/1422-0067/27/21/9855
AB - Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with resistance to androgen-deprivation therapy (ADT) being the major clinical challenge. A key driver of this resistance is transcriptional reprogramming, during which androgen receptor (AR) activity shifts from ligand-dependent signaling to reactivation via splice variants such as AR-V7 and eventually to AR-negative states. The oncogene c-MYC plays a pivotal role through context-dependent crosstalk with AR, suppressing canonical AR-dependent transcription while promoting its own oncogenic program. This reprogramming is sustained by dysregulation of RB1/E2F, NF-κB, PI3K/AKT/mTOR, WNT/β-catenin, and Hippo/YAP/TAZ pathways, alongside N-MYC and L-MYC activation, forming an interconnected network driving phenotypic plasticity. This review focuses on cyclin-dependent kinases 8 and 19 (CDK8/19), components of the Mediator complex kinase module, as potential regulators of epigenetic plasticity in PCa capable of modulating both AR-dependent and AR-independent transcription. Preclinical studies show that CDK8/19 inhibition suppresses castration-resistant prostate cancer (CRPC) xenograft growth, restores ADT sensitivity, and additively enhances enzalutamide even in AR-V7-expressing resistant models, though the mechanisms of CDK8/19-mediated AR regulation remain largely undefined. We analyze the signaling pathways driving AR activity changes during PCa progression, evaluate potential mechanisms of CDK8/19-mediated AR regulation, and assess the therapeutic potential of CDK8/19 inhibitors with ADT.
SN - 1422-0067
ER -