Overexpression of REST Represses the Epithelial-Mesenchymal Transition Process and Decreases the Aggressiveness of Prostate Cancer Cells

• Published in: International journal of molecular sciences 2024-03, Vol.25 (6), p.3332
• Main Authors: Indo, Sebastián, Orellana-Serradell, Octavio, Torres, María José, Castellón, Enrique A, Contreras, Héctor R
• Format: Article
• Language: English
• Subjects: Androgen Antagonists; Androgens; Benzamides; Cancer; Cancer therapies; Cell Line, Tumor; Diagnosis; Epithelial-Mesenchymal Transition - genetics; epithelial–mesenchymal transition (EMT); Genes; Genotype & phenotype; Health aspects; Humans; Ligands; Male; Medical prognosis; Metastasis; Morphology; neuroendocrine PCa (NEPC); Nitriles; Phenylthiohydantoin; Prostate cancer; prostate cancer (PCa); Prostatic Neoplasms - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Proteins; RE-1 silencing transcription factor (REST); Receptors, Androgen - metabolism; Stem cells; Transcription Factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063332

The RE-1 silencing transcription factor (REST) is a repressor factor related to neuroendocrine prostate cancer (PCa) (NEPC), a poor prognostic stage mainly associated with castration-resistant PCa (CRPC). NEPC is associated with cell transdifferentiation and the epithelial-mesenchymal transition (EMT) in cells undergoing androgen deprivation therapy (ADT) and enzalutamide (ENZ). The effect of REST overexpression in the 22rv1 cell line (xenograft-derived prostate cancer) on EMT, migration, invasion, and the viability for ENZ was evaluated. EMT genes, Twist and Zeb1, and the androgen receptor (AR) were evaluated through an RT-qPCR and Western blot in nuclear and cytosolic fractions of REST-overexpressing 22rv1 cells (22rv1-REST). The migratory and invasive capacities of 22rv1-REST cells were evaluated via Transwell assays with and without Matrigel, respectively, and their viability for enzalutamide via MTT assays. The 22rv1-REST cells showed decreased nuclear levels of Twist, Zeb1, and AR, and a decreased migration and invasion and a lower viability for ENZ compared to the control. Results were expressed as the mean + SD of three independent experiments (Mann-Whitney U test, Kruskal-Wallis, Tukey test). REST behaves like a tumor suppressor, decreasing the aggressiveness of 22rv1 cells, probably through the repression of EMT and the neuroendocrine phenotype. Furthermore, REST could represent a response marker to ENZ in PCa patients.