title: JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner.
abstract: Tumors characterized by an intense ribosome biogenesis often display a more aggressive behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, including the epigenetic regulation of the condensation of chromatin portions containing rRNA genes. JHDM1B (Jumonji C histone demethylase 1B) is a histone demethylase able to regulate the accessibility of rRNA genes. In this study, we aimed to define the contribution of JHDM1B expression to the features of breast cancer, a tumor type whose behavior is related to the rate of ribosome biogenesis. We show that, in breast cancer-derived cell lines, the increase in rRNA transcription that follows JHDM1B knock-down is mirrored by an augmented cell proliferation only in p53 compromised cells, while p53 competent cells undergo cellular senescence and death. The latter effect appears to be mediated by a p38-dependent phosphorylation of p53, inducing the expression of p15(Ink4b) and p21(Waf1). In breast cancers, lower JHDM1B expression correlates with an increased size of specifically stained nucleolar organized regions, a morphological parameter directly related to the rate of ribosome biogenesis and with a poorer prognosis. In addition, in tumors lacking the controller function of p53, a lower expression of JHDM1B is associated with an increased tumor size at diagnosis. Altogether, our data indicate that epigenetic activation of rDNA genes induced by JHDM1B depletion is associated with a p53-dependent growth arrest, but may promote cancer cell growth when p53 is lacking.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Penzo
authors.forename: Lucia
authors.initials: L
authors.lastname: Casoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Pollutri
authors.forename: Laura
authors.initials: L
authors.lastname: Sicuro
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Mario
authors.initials: M
authors.lastname: Taffurelli
authors.forename: Marzia
authors.initials: M
authors.lastname: Govoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.forename: Davide
authors.initials: D
authors.lastname: Trerè
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Montanaro
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D016922:Cellular Senescence; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human
keywords: JHDM1B; breast cancer; p38MAPK; p53; ribosome biogenesis