1. PAF1-mediated transcriptional reprogramming confers docetaxel resistance in advanced prostate cancer.
- Author
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Muniyan S, Vengoji R, Nimmakayala RK, Seshacharyulu P, Perumalsamy B, Alsafwani ZW, Kakar SS, Smith LM, Shonka N, Teply BA, Lele SM, Ponnusamy MP, and Batra SK
- Subjects
- Humans, Male, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Neoplastic Stem Cells metabolism, Transcription Factors genetics, Transcription Factors metabolism, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Antineoplastic Agents pharmacology, Nuclear Proteins genetics, Nuclear Proteins metabolism, Organoids metabolism, Organoids drug effects, Animals, Docetaxel pharmacology, Drug Resistance, Neoplasm genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism
- Abstract
Advanced prostate cancer (PCa) remains a significant clinical challenge, and docetaxel plays a significant role in disease management. Despite the efficacy of docetaxel as a first-line chemotherapy, resistance often develops. We developed three clinically relevant in vitro PCa cell models and transcriptomic analysis identified that the Paf1/RNA polymerase II complex component (PAF1)-associated pluripotent-transcription factor (TF), SOX2, plays a crucial role in docetaxel resistance. The cancer stem cell (CSC) transcriptional master regulator PAF1 is significantly higher in PCa cell lines, tumor tissues, and docetaxel resistant (DR) PCa cells than in age-matched control cells. To determine the molecular underlying and functional characteristics of PAF1 in resistance mechanisms, we performed coimmunoprecipitation, embryonic stem cell network proteins, in vitro tumor-initiating ability, and 3D multicellular organoid growth using PAF1 knockdown cells. Tet-inducible PAF1 depletion reduced the drug-efflux phenotype, tumor-initiating frequencies, and three-dimensional organoid growth of the docetaxel-resistant PCa cell lines. Functional studies also showed restoration of docetaxel sensitivity in a 3D tumorsphere model upon PAF1 depletion. PAF1 depletion was also associated with decreased pluripotent TFs and other CSC markers. This study provides a novel regulatory mechanism of docetaxel resistance in PCa through PAF1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKB is a founding member of Sanguine Diagnostics and Therapeutics, Inc. Other authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2025
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