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: Marianna Penzo, Lucia Casoli, Daniela Pollutri, Laura Sicuro, Claudio Ceccarelli, Donatella Santini, Mario Taffurelli, Marzia Govoni, Daniela Brina, Davide Trerè, Lorenzo Montanaro
• Journal: International journal of cancer (Int J Cancer) Vol. 136 Issue 5 Pg. E272-81 (Mar 01 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 25273595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 UICC.

Chemical References

• F-Box Proteins
• RNA, Messenger
• RNA, Ribosomal
• RNA, Small Interfering
• TP53 protein, human
• Tumor Suppressor Protein p53
• Jumonji Domain-Containing Histone Demethylases
• KDM2A protein, human

Topics

• Blotting, Western
• Breast Neoplasms (metabolism, mortality, pathology)
• Cell Proliferation
• Cellular Senescence
• F-Box Proteins (antagonists & inhibitors, genetics, metabolism)
• Female
• Humans
• Immunoenzyme Techniques
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (genetics)
• RNA, Ribosomal (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Ribosomes (metabolism)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)