Abstract
Transforming growth factor β (TGFβ) is a key regulator of epithelial-to-mesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGFβ, on ΕΜΤ, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGFβ stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGFβ receptor I (TβRI) and the transcriptional repressor Hes1. Mutation of Snail1 lysine residue 234 to arginine (K234R) abolished sumoylation of Snail1, as well as its migratory and invasive properties in human prostate cancer cells. An increased immunohistochemical expression of Snail1, Sumo1, TβRI, Hes1, and c-Jun was observed in aggressive prostate cancer tissues, consistent with their functional roles in tumorigenesis.
Highlights
Transforming growth factor beta (TGFβ) is a versatile cytokine implicated in crucial cellular processes such as embryogenesis, differentiation, proliferation, apoptosis, and tissue repair [1, 2]
To investigate whether Snail1 regulates the expression of TGFβ receptor I (TβRI), we silenced the endogenous expression of Snail1 by using siRNA or non-targeting control siRNA in PC-3U cells and probed with antibodies directed against TβRI
Because receptor-associated Smads (R-Smads) (Smad2, Smad3) are the downstream regulators of TβRI, we investigated the effects of silencing of Snail1, on the phosphorylation of Smad2 by using phospho-specific antibodies; treatment with siSnail1 reduced the phosphorylation of Smad2 (Figure 1A)
Summary
Transforming growth factor beta (TGFβ) is a versatile cytokine implicated in crucial cellular processes such as embryogenesis, differentiation, proliferation, apoptosis, and tissue repair [1, 2]. TGFβ was later found to inhibit proliferation of epithelial cells and maintain their homeostasis; TGFβ has both pro-tumorigenic and tumor suppressive effects [1, 3,4,5]. TGFβ exhibits its growth-suppressive effects at initial stages by limiting cell proliferation and cell migration, and inducing apoptosis in normal epithelial cells [6, 7]. TGFβ promotes tumor growth by evading these inhibitory signals and instead triggering other cellular processes such as the epithelial-to-mesenchymal transition (EMT), enabling cells to become motile and traverse to distant organs and metastasize [6, 8]. TGFβ signals by forming a heterotetrameric complex of two types of serine/threonine receptor kinases, the TGFβ receptors (TβRs) II and I [9]. The trimeric Smad complexes translocate to the nucleus and promote TGFβ-induced transcriptional responses by binding to the Smad Binding Elements (SBEs) composed of the sequence CAGACA on the DNA [13, 14]
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