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Characterization of sonic hedgehog as a novel NF-B target gene that promotes NF-B-mediated apoptosis resistance and tumor growth in vivo

Hubert Kasperczyk^*, Bernd Baumann, Klaus-Michael Debatin^* and Simone Fulda^*,1

^* University Children’s Hospital, Ulm, Germany; and

Institute of Physiological Chemistry, Ulm University, Ulm, Germany

¹ Correspondence: University Children’s Hospital, Eythstr. 24, D-89075 Ulm, Germany. E-mail: simone.fulda{at}uniklinik-ulm.de

To explore mechanisms controlling sonic hedgehog (Shh) expression in human cancers, we investigated regulation of Shh by the transcription factor NF-B. We identify putative NF-B binding sites in the human Shh promoter region that specifically bind NF-B complexes. Further, NF-B activation by tumor necrosis factor (TNF-) or p65 overexpression stimulates Shh promoter activity and p65 binds to Shh promoter in vivo. NF-B-mediated transcriptional activation of Shh is mapped to a minimal NF-B consensus site at position +139 of Shh promoter. NF-B activation results in increased Shh mRNA and protein expression in vitro and, notably, also in vivo in a genetic mouse model of inducible NF-B activity. Specific NF-B inhibition by inhibitory NF-B (I-B) superrepressor or p65 knockdown inhibits NF-B-induced Shh promoter activation and Shh expression. NF-B-mediated Shh expression promotes proliferation and confers resistance to TRAIL-induced apoptosis. Silencing of Shh prevents NF-B-stimulated proliferation, while the addition of Shh rescues the proliferation defect imposed by NF-B inhibition. Notably, NF-B-stimulated tumor growth is significantly impaired by Shh knockdown in an in vivo model of pancreatic cancer. By demonstrating that NF-B regulates Shh expression, which contributes to NF-B-mediated proliferation and apoptosis resistance in vitro and in vivo, our findings have important implications to target aberrant Shh expression in human cancers.—Kasperczyk, H., Baumann, B., Debatin, K.-M., Fulda, S. Characterization of sonic hedgehog as a novel NF-B target gene that promotes NF-B-mediated apoptosis resistance and tumor growth in vivo.

Key Words: cancer • cell death