Regulation of non-AU-rich element containing c-fms proto-oncogene expression by HuR in breast cancer

H. H. Woo, Y. Zhou, X. Yi, C. L. David, Wenxin - Zheng, M. Gilmore-Hebert, H. M. Kluger, E. C. Ulukus, T. Baker, J. B. Stoffer, Setsuko K Chambers

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The role of RNA-binding proteins in cancer biology is recognized increasingly. The nucleocytoplasmic shuttling and AU-rich RNA-binding protein HuR stabilizes several cancer-related target mRNAs. The proto-oncogene c-fms, whose 3′untranslated region (3′UTR) is not AU-rich, is associated with poor prognosis in breast cancer. Using a large breast-cancer tissue array (N=670), we found nuclear HuR expression to be associated with nodal metastasis and independently with poor survival (P=0.03, RR 1.45), as well as to be co-expressed with c-fms in the breast tumors (P=0.0007). We described c-fms mRNA as a direct target of HuR in vivo, and that HuR bound specifically to a 69-nt region containing 'CUU' motifs in 3′UTR c-fms RNA. Overexpressing or silencing HuR significantly up- or down-regulated c-fms RNA expression, respectively. We also found that known glucocorticoid stimulation of c-fms RNA and protein is largely dependent on the presence of HuR. HuR, by binding to the 69-nt wild type, but not mutant, c-fms sequence can regulate reporter gene expression post-transcriptionally. We are the first to describe that HuR can regulate gene expression by binding non-AU-rich sequences in 3′UTR c-fms RNA. Collectively, our findings suggest that HuR plays a supportive role for c-fms in breast cancer progression by binding a 69-nt element in its 3′UTR, thus regulating its expression.

Original languageEnglish (US)
Pages (from-to)1176-1186
Number of pages11
JournalOncogene
Volume28
Issue number9
DOIs
Publication statusPublished - Mar 5 2009

    Fingerprint

Keywords

  • Breast cancer
  • c-fms proto-oncogene
  • HuR
  • Posttranscriptional regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this