Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6 Promoting Invasion of Prostate Cancer Cells.

Noopur Thakur,Maréne Landström,Jie Song,Carl-Henrik Heldin,Susumu Itoh,Anahita Hamidi,Anders Bergh

doi:10.1016/j.isci.2020.101470

Abstract

SummaryTransforming 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.

Highlights

Transforming growth factor b (TGF-b) is a pleiotropic cytokine that regulates cellular responses, such as proliferation and migration, during embryonal development and tissue homeostasis; in addition, TGF-b signaling is perturbed in diseases, including tumorigenesis (Bierie and Moses, 2006; Derynck and Akhurst, 2007; Heldin and Moustakas, 2016; Massague, 2012)
We report an additional function of Smad7, i.e., to enhance TGF-b induction of c-Jun and Histone deacetylase 6 (HDAC6) via binding to their regulatory regions, promoting migration and invasion of prostate cancer cells
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

Summary

Introduction

TGF-b is a pleiotropic cytokine that regulates cellular responses, such as proliferation and migration, during embryonal development and tissue homeostasis; in addition, TGF-b signaling is perturbed in diseases, including tumorigenesis (Bierie and Moses, 2006; Derynck and Akhurst, 2007; Heldin and Moustakas, 2016; Massague, 2012). TGF-b signals through type I (TbRI) and type II (TbRII) serine/threonine kinase receptors leading to phosphorylation of R-Smads (Smad and Smad3), which form complexes with Smad that are translocated to the nucleus to regulate transcription of genes. TGF-b activates non-Smad signaling pathways (Edlund et al, 2003), in which the tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is crucial (Gudey et al, 2014; Hamidi et al, 2017; Mu et al, 2011; Sorrentino et al, 2008; Yamashita et al, 2008). The C-terminal region of Smad has a conserved Mad homology 2 (MH2) domain but lacks the SXS motif, which in R-Smads is phosphorylated by TbRI. The N-terminal MH1 domain, which is involved in the DNA binding of Smad and 4, is only partially conserved in Smad (Aragon et al, 2019; Heldin et al, 1997)

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