Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene

Cheryl M. Koh, Bora Gurel, Siobhan Sutcliffe, Martin J. Aryee, Denise Schultz, Tsuyoshi Iwata, Motohide Uemura, Karen I. Zeller, Uzoma Anele, Qizhi Zheng, Jessica L. Hicks, William G Nelson, Chi V. Dang, S Yegnasubramanian, Angelo Michael Demarzo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1824-1834
Number of pages11
JournalAmerican Journal of Pathology
Volume178
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Oncogenes
Prostate
Gene Expression
Prostatic Neoplasms
Neoplasms
Adenocarcinoma
Epithelial Cells
Prostatic Intraepithelial Neoplasia
Ribosomal RNA
Maintenance
Survival
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. / Koh, Cheryl M.; Gurel, Bora; Sutcliffe, Siobhan; Aryee, Martin J.; Schultz, Denise; Iwata, Tsuyoshi; Uemura, Motohide; Zeller, Karen I.; Anele, Uzoma; Zheng, Qizhi; Hicks, Jessica L.; Nelson, William G; Dang, Chi V.; Yegnasubramanian, S; Demarzo, Angelo Michael.

In: American Journal of Pathology, Vol. 178, No. 4, 04.2011, p. 1824-1834.

Research output: Contribution to journalArticle

Koh, CM, Gurel, B, Sutcliffe, S, Aryee, MJ, Schultz, D, Iwata, T, Uemura, M, Zeller, KI, Anele, U, Zheng, Q, Hicks, JL, Nelson, WG, Dang, CV, Yegnasubramanian, S & Demarzo, AM 2011, 'Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene', American Journal of Pathology, vol. 178, no. 4, pp. 1824-1834. https://doi.org/10.1016/j.ajpath.2010.12.040
Koh, Cheryl M. ; Gurel, Bora ; Sutcliffe, Siobhan ; Aryee, Martin J. ; Schultz, Denise ; Iwata, Tsuyoshi ; Uemura, Motohide ; Zeller, Karen I. ; Anele, Uzoma ; Zheng, Qizhi ; Hicks, Jessica L. ; Nelson, William G ; Dang, Chi V. ; Yegnasubramanian, S ; Demarzo, Angelo Michael. / Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. In: American Journal of Pathology. 2011 ; Vol. 178, No. 4. pp. 1824-1834.
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AU - Schultz, Denise

AU - Iwata, Tsuyoshi

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AU - Hicks, Jessica L.

AU - Nelson, William G

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