Abstract 5145: KDM2B expression regulates ribosome biogenesis and cancer cell growth in a p53-dependent manner

Abstract

Abstract Ribosome biogenesis is a cellular process requiring a fine-tuned control, as its deregulation is linked to cancer progression. Indeed, tumors characterized by an intense ribosome biogenesis often display a more aggressive biological and clinical behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, the higher one being the epigenetic regulation of chromatin portions containing rRNA genes. KDM2B (Lysine (K)-specific demethylase 2B) is a histone demethylase modulating the accessibility of rRNA genes, thereby repressing their transcription. In particular KDM2B is known to specifically act on trimethylated K4 of histone H3 (H3K4) associated with rDNA. In this study we aimed to define the contribution of KDM2B expression to the biological features of breast cancer, a tumor type whose clinical behavior is known to be related to the rate of ribosome biogenesis. We show that, in primary breast carcinomas, lower KDM2B expression correlates with an increased size of specifically stained nucleolar organizer regions, a morphological parameter directly related to the rate of ribosome biogenesis, and with a poorer prognosis. In vitro, in breast cancer-derived cell lines, siRNA mediated KDM2B knock-down (KD) induced an increase in H3K4 trimethylation and in rRNA transcription. However, this 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-mediated phosphorylation of p53, inducing the expression of p15Ink4b and p21Waf1, and is not linked to p53 stabilization. In the long term, stable KDM2B KD in p53-compromised breast cancer cells induced a series of additional biological features including their augmented cellular clonogenic potential and invasive capability. Altogether our data indicate that abnormal JHDM1B-mediated epigenetic activation of rDNA genes elicits a p53-mediated growth arrest, but may promote cancer cell growth when p53 is lacking. Citation Format: Marianna Penzo, Lucia Casoli, Laura Sicuro, Alice Galibiati, Daniela Pollutri, Marzia Govoni, Claudio Ceccarelli, Donatella Santini, Mario Taffurelli, Davide Treré, Lorenzo Montanaro. KDM2B expression regulates ribosome biogenesis and cancer cell growth in a p53-dependent manner. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5145. doi:10.1158/1538-7445.AM2014-5145