KLF5 and NFYA factors as novel regulators of prostate cancer cell metabolism
| Autor: | Charles Joly-Beauparlant, Arnaud Droit, Martin Pelletier, Camille Lafront, Cindy Weidmann, Virginie Paquette, Raghavendra Tejo Karthik Poluri, Étienne Audet-Walsh, Chantal Guillemette, Eric P. Allain |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Endocrinology Diabetes and Metabolism Cell Kruppel-Like Transcription Factors Biology 03 medical and health sciences 0302 clinical medicine Endocrinology Cell Line Tumor medicine Humans Transcription factor Gene Cell Proliferation Gene knockdown Cell growth Prostatic Neoplasms Cell biology Androgen receptor Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology Nuclear receptor CCAAT-Binding Factor Receptors Androgen 030220 oncology & carcinogenesis Androgens Reprogramming Transcription Factors |
| Zdroj: | Endocrine-related cancer. 28(4) |
| ISSN: | 1479-6821 |
| Popis: | Prostate cancer (PCa) cells rely on the androgen receptor (AR) signaling axis to reprogram metabolism to sustain aberrant proliferation. Whether additional transcription factors participate to this reprogramming remains mostly unknown. To identify such factors, DNA motif analyses were performed in the promoter and regulatory regions of genes sensitive to androgens in PCa cells. These analyses identified two transcription factors, KLF5 and NFYA, as possibly associated with PCa cell metabolism. In clinical datasets, KLF5 and NFYA expression levels were associated with disease aggressiveness, being significantly decreased and increased, respectively, during PCa progression. Their expression was next investigated by qPCR and Western blot in human PCa cell models, revealing a positive regulation of KLF5 by androgens and a correlation between NFYA and AR protein expression status. siRNA-mediated knockdown of KLF5 increased human PCa cell proliferation rate in AR-positive cell models, suggesting a tumor suppressor function. Live-cell metabolic assays showed that knockdown of KLF5 promoted mitochondrial respiration, a key metabolic pathway associated with PCa progression. The opposite was observed for knockdown of NFYA regarding proliferation and respiration. RNA-seq analyses following the knockdown of either KLF5 and NFYA confirmed that both factors regulated distinct metabolic gene signatures, as well as other gene signatures, explaining their differential impact on PCa cell proliferation and metabolism. Overall, our findings identify KLF5 and NFYA as novel regulators of PCa cell metabolism. |
| Databáze: | OpenAIRE |
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