Essential role of JunD in cell proliferation is mediated via MYC signaling in prostate cancer cells

• Published in: Cancer letters 2019-04, Vol.448, p.155-167
• Main Authors: Elliott, Bethtrice, Millena, Ana Cecilia, Matyunina, Lilya, Zhang, Mengnan, Zou, Jin, Wang, Guangdi, Zhang, Qiang, Bowen, Nathan, Eaton, Vanessa, Webb, Gabrielle, Thompson, Shadyra, McDonald, John, Khan, Shafiq
• Format: Article
• Language: English
• Subjects: Apoptosis; c-MYC; c-Myc protein; Cancer initiation; Cancer therapies; Carcinogenesis; Cell cycle; Cell Cycle - physiology; Cell cycle regulation; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - physiology; CRISPR; Cyclin D1; Cyclin-dependent kinase 2; Disease; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Humans; Immunoglobulins; JunD; Kinases; Male; Medical prognosis; Metastasis; Microarray Analysis; Morphology; Mutation; Myc protein; Overexpression; Prostate cancer; Prostatic Neoplasms - metabolism; Protein synthesis; Proteins; Proteomics; Proto-Oncogene Proteins c-jun - physiology; Proto-Oncogene Proteins c-myc - physiology; Quantitative analysis; Signal Transduction - physiology; Transcription factors
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2019.02.005

JunD, a member of the AP-1 family, is essential for cell proliferation in prostate cancer (PCa) cells. We recently demonstrated that JunD knock-down (KD) in PCa cells results in cell cycle arrest in G1-phase concomitant with a decrease in cyclin D1, Ki67, and c-MYC, but an increase in p21 levels. Furthermore, the over-expression of JunD significantly increased proliferation suggesting JunD regulation of genes required for cell cycle progression. Here, employing gene expression profiling, quantitative proteomics, and validation approaches, we demonstrate that JunD KD is associated with distinct gene and protein expression patterns. Comparative integrative analysis by Ingenuity Pathway Analysis (IPA) identified 1) cell cycle control/regulation as the top canonical pathway whose members exhibited a significant decrease in their expression following JunD KD including PRDX3, PEA15, KIF2C, and CDK2, and 2) JunD dependent genes are associated with cell proliferation, with MYC as the critical downstream regulator. Conversely, JunD over-expression induced the expression of the above genes including c-MYC. We conclude that JunD is a crucial regulator of cell cycle progression and inhibiting its target genes may be an effective approach to block prostate carcinogenesis. •JunD regulates genes required for cell cycle progression in PCa cells.•JunD knockdown decreases the expression of genes involved in cell cycle regulation.•The cell cycle regulatory JunD dependent genes act upstream and down-stream of c-MYC.•JunD effects on cell proliferation are blocked by c-MYC inhibitor.•Overexpression of JunD increases proliferation and expression of JunD dependent genes.