title: HES6 promotes prostate cancer aggressiveness independently of Notch signalling.
abstract: Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high-grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer-specific up-regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up- and down-regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor-independent manner. Using a Notch-sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell-autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression.
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Filipe L F
authors: FL
authors: Carvalho
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Luigi
authors: L
authors: Marchionni
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Anuj
authors: A
authors: Gupta
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Basheer A
authors: BA
authors: Kummangal
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Brady Institute of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Edward M
authors: EM
authors: Schaeffer
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Brady Institute of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Ashley E
authors: AE
authors: Ross
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Brady Institute of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Departments of Pathology and Molecular Medicine and Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON, Canada.
authors: David M
authors: DM
authors: Berman
mesh_terms: D000728:Androgens / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000728:Androgens; D051792:Basic Helix-Loop-Helix Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D012097:Repressor Proteins; C411859:HES6 protein, human; C499374:NOTCH3 protein, human
keywords: Gleason score; HES6; NOTCH3; Notch pathway; prostate cancer