Runx2 regulates survivin expression in prostate cancer cells.
Previously we described that bone morphogenetic protein-7 (BMP7) could protect prostate cancer C4-2B cells from serum starvation-induced apoptosis via survivin induction. Here, for the first time, we identify Runx2 as a key regulator of survivin transcription. In C4-2B cells grown normally, suppression of Runx2 reduced survivin expression. Using ChIP assays, two regions of the survivin promoter, -1953 to -1812 (I) and -1485 to -1119 (II) encompassing consensus Runx-binding sites were examined. Runx2 was found to be associated with both regions, with a stronger affinity to region-I. In serum-starved cells neither region was occupied, but BMP7 restored association to region-II and not region-I. In reporter assays, transcription activity by BMP7 was significantly reduced when sequences including binding sites of region-II were deleted. Additionally, Runx2 expression was enhanced by BMP7 in these cells. Along with a strong survivin expression, a trend in increased Runx2 expression in human prostate cancer cells and tissues was noted. In the conditional Pten-knockout mouse, Runx2 level increased with growth of prostate tumor. The data define a novel role of Runx2 in regulating survivin expression in malignant epithelial cells and identify it as a critical factor in BMP signaling that protects cancer cells against apoptosis.
Lim
Minyoung
M
Programs in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Zhong
Chen
C
Yang
Shangxin
S
Bell
Adam M
AM
Cohen
Michael B
MB
Roy-Burman
Pradip
P
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D055419:Bone Morphogenetic Protein 7 / Q000502:physiology; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D040081:Protein Array Analysis; D000077022:Survivin; D014162:Transfection; D015854:Up-Regulation
C107489:BIRC5 protein, human; D055419:Bone Morphogenetic Protein 7; D050659:Core Binding Factor Alpha 1 Subunit; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C493709:RUNX2 protein, human; D000077022:Survivin