title: 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.
authors: Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21231 , USA.
authors: Cheryl M
authors: CM
authors: Koh
authors: Bora
authors: B
authors: Gurel
authors: Siobhan
authors: S
authors: Sutcliffe
authors: Martin J
authors: MJ
authors: Aryee
authors: Denise
authors: D
authors: Schultz
authors: Tsuyoshi
authors: T
authors: Iwata
authors: Motohide
authors: M
authors: Uemura
authors: Karen I
authors: KI
authors: Zeller
authors: Uzoma
authors: U
authors: Anele
authors: Qizhi
authors: Q
authors: Zheng
authors: Jessica L
authors: JL
authors: Hicks
authors: William G
authors: WG
authors: Nelson
authors: Chi V
authors: CV
authors: Dang
authors: Srinivasan
authors: S
authors: Yegnasubramanian
authors: Angelo M
authors: AM
authors: De Marzo
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008297:Male; D051379:Mice; D008854:Microscopy, Electron / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D011467:Prostate; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc