Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6 Promoting Invasion of Prostate Cancer Cells
Noopur Thakur, Anahita Hamidi, Jie Song, Susumu Itoh, Anders Bergh, Carl‐Henrik Heldin, Maréne Landström
Abstract
Transforming growth factor b (TGF-b) enhances migration and invasion of cancer cells, causing life-threatening metastasis. Smad7 expression is induced by TGF-b to control TGF-b signaling in a negative feedback manner. Here we report an additional function of Smad7, i.e., to enhance TGF-b induction of c-Jun and HDAC6 via binding to their regulatory regions, promoting migration and invasion of prostate cancer cells. Lysine 102 in Smad7 is crucial for binding to specific consensus sites in c-Jun and HDAC6, even when endogenous Smad2, 3, and 4 were silenced by siRNA. A correlation between the mRNA expression of Smad7 and HDAC6, Smad7 and c-Jun, and c-Jun and HDAC6 was found in public databases from analyses of prostate cancer tissues. High expression of Smad7, HDAC6, and c-Jun correlated with poor prognosis for patients with prostate cancer. The knowledge that Smad7 can activate transcription of proinvasive genes leading to prostate cancer progression provides clinically relevant information.