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
Affiliations
Noopur Thakur
Ludwig Institute for Cancer Research, Ltd., Science for Life Laboratory, Uppsala University, Box 595, 751 24 Uppsala, Sweden
Anahita Hamidi
Ludwig Institute for Cancer Research, Ltd., Science for Life Laboratory, Uppsala University, Box 595, 751 24 Uppsala, Sweden; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, 751 23 Uppsala, Sweden
Jie Song
Department of Medical Biosciences, Umeå University, 901 87 Umeå, Sweden
Susumu Itoh
Laboratory of Biochemistry, Showa Pharmaceutical University, Tokyo 194-8543, Japan
Anders Bergh
Department of Medical Biosciences, Umeå University, 901 87 Umeå, Sweden
Carl-Henrik Heldin
Ludwig Institute for Cancer Research, Ltd., Science for Life Laboratory, Uppsala University, Box 595, 751 24 Uppsala, Sweden; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, 751 23 Uppsala, Sweden; Corresponding author
Maréne Landström
Ludwig Institute for Cancer Research, Ltd., Science for Life Laboratory, Uppsala University, Box 595, 751 24 Uppsala, Sweden; Department of Medical Biosciences, Umeå University, 901 87 Umeå, Sweden; Corresponding author
Summary: Transforming growth factor β (TGF-β) enhances migration and invasion of cancer cells, causing life-threatening metastasis. Smad7 expression is induced by TGF-β to control TGF-β signaling in a negative feedback manner. Here we report an additional function of Smad7, i.e., to enhance TGF-β 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.
