Alterations in Nucleolar Structure and Gene Expression Programs in Prostatic Neoplasia Are Driven by the MYC Oncogene

Abstract

Increased nucleolar size and number are hallmark features of many cancers. In prostate cancer, nucleolar enlargement and increased numbers are some of the earliest morphological changes associated with development of premalignant prostate intraepithelial neoplasia (PIN) lesions and invasive adenocarcinomas. However, the molecular mechanisms that induce nucleolar alterations in PIN and prostate cancer remain largely unknown. We verify that activation of the MYC oncogene, which is overexpressed in most human PIN and prostatic adenocarcinomas, leads to formation of enlarged nucleoli and increased nucleolar number in prostate luminal epithelial cells in vivo. In prostate cancer cells in vitro, MYC expression is needed for maintenance of nucleolar number, and a nucleolar program of gene expression. To begin to decipher the functional relevance of this transcriptional program in prostate cancer, we examined FBL (encoding fibrillarin), a MYC target gene, and report that fibrillarin is required for proliferation, clonogenic survival, and proper ribosomal RNA accumulation/processing in human prostate cancer cells. Further, fibrillarin is overexpressed in PIN lesions induced by MYC overexpression in the mouse prostate, and in human clinical prostate adenocarcinoma and PIN lesions, where its expression correlates with MYC levels. These studies demonstrate that overexpression of the MYC oncogene increases nucleolar number and size and a nucleolar program of gene expression in prostate epithelial cells, thus providing a molecular mechanism responsible for hallmark nucleolar alterations in prostatic neoplasia.

Cancer Cell Metabolism: There Is No ROS for the Weary

“…Hence, the proto-oncogene responds to nutrient availability, whereas the deregulated oncogene, through gene amplification or chromosomal translocation, for example, severs its ties to the external world, inducing a constitutive growth program that is addicted to nutrients. In this regard, it is notable that MYC expression is elevated in patients with prostate cancer and that MYC plays a central role in murine models of prostate cancer and maintenance of human prostate cancer, such that knockdown of MYC expression results in diminished prostate cancer cell proliferation (5).…”

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

“…14 Increased rDNA expression is associated with chromatin decondensation at the rDNA locus and enlarged nucleoli. 15,16 We therefore checked whether the mutant UBF affects nucleolar architecture. Cells of an affected individual and control were methanol-fixed and subjected to immunofluorescence staining using antibodies recognizing the nucleolar marker nucleolin (Abcam ab50279).…”

Novel Assay to Detect RNA Polymerase I Activity In Vivo

“…More recent studies have shown that this increased size correlates with increased levels of the 45S/5′ETS as well as 5.8S, 18S and 28S rRNA levels (15). Further, prostate cancers have frequent overexpression of MYC which regulates nucleolar size, and common loss of PTEN, which can also activate Pol I transcription and effect nucleolar size and function (27–29). …”