Genome-wide Runx2 occupancy in prostate cancer cells suggests a role in regulating secretion

Gillian H. Little*, Houtan Noushmehr, Sanjeev K. Baniwal, Benjamin P. Berman, Gerhard A. Coetzee, Baruch Frenkel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Runx2 is a metastatic transcription factor (TF) increasingly expressed during prostate cancer (PCa) progression. Using PCa cells conditionally expressing Runx2, we previously identified Runx2-regulated genes with known roles in epithelial-mesenchymal transition, invasiveness, angiogenesis, extracellular matrix proteolysis and osteolysis. To map Runx2-occupied regions (R2ORs) in PCa cells, we first analyzed regions predicted to bind Runx2 based on the expression data, and found that recruitment to sites upstream of the KLK2 and CSF2 genes was cyclical over time. Genome-wide ChIP-seq analysis at a time of maximum occupancy at these sites revealed 1603 high-confidence R2ORs, enriched with cognate motifs for RUNX, GATA and ETS TFs. The R2ORs were distributed with little regard to annotated transcription start sites (TSSs), mainly in introns and intergenic regions. Runx2-upregulated genes, however, displayed enrichment for R2ORs within 40kb of their TSSs. The main annotated functions enriched in 98 Runx2-upregulated genes with nearby R2ORs were related to invasiveness and membrane trafficking/secretion. Indeed, using SDS-PAGE, mass spectrometry and western analyses, we show that Runx2 enhances secretion of several proteins, including fatty acid synthase and metastasis-associated laminins. Thus, combined analysis of Runx2's transcriptome and genomic occupancy in PCa cells lead to defining its novel role in regulating protein secretion.

Original languageAmerican English
Pages (from-to)3538-3547
Number of pages10
JournalNucleic Acids Research
Volume40
Issue number8
DOIs
StatePublished - Apr 2012
Externally publishedYes

Bibliographical note

Funding Information:
National Institutes of Health (NIH) (DK07112 to B.F. and CA109147 to G.A.C.). H.N. is supported by NIH training grant 5T32CA009320-27. B.F. holds the J. Harold and Edna L. LaBriola Chair in Genetic Orthopedic Research at USC. Funding for open access charge: NIH DK07112.

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