Gamma synuclein is a novel Twist1 target that promotes TGF-β-induced cancer cell migration and invasion

Abstract

Transforming growth factor β (TGF-β) is critical for embryonic development, adult tissue homeostasis, and tumor progression. TGF-β suppresses tumors at early stage, but promotes metastasis at later stage through oncogenes such as Twist1. Gamma-synuclein (SNCG) is overexpressed in a variety of invasive and metastatic cancer. Here, we show that TGF-β induces SNCG expression by Smad-Twist1 axis, thus promoting TGF-β- and Twist1-induced cancer cell migration and invasion. We identify multiple Twist1-binding sites (E-boxes) in SNCG promoter. Chromatin immunoprecipitation and luciferase assays confirm the binding of Twist1 to the E-boxes of SNCG promoter sequence (−129/−1026 bp). Importantly, the Twist1-binding site close to the transcription initiation site is critical for the upregulation of SNCG expression by TGF-β and Twist1. Mutations of Twist1 motif on the SNCG promoter constructs markedly reduces the promoter activity. We further show that TGF-β induces Twist1 expression through Smad thereby enhancing the binding of Twist1 to SNCG promoter, upregulating SNCG promoter activity and increasing SNCG expression. SNCG knockdown abrogates TGF-β- or Twist1-induced cancer cell migration and invasion. Finally, SNCG knockdown inhibits the promotion of cancer metastasis by Twist1. Together, our data demonstrate that SNCG is a novel target of TGF-β-Smad-Twist1 axis and a mediator of Twist1-induced cancer metastasis.

Nodal regulates bladder cancer cell migration and invasion via the ALK/Smad signaling pathway

“…Emerging evidence shows that TGF-β/ALK/Smad signaling plays a role in carcinogenesis in many cancer types. 24 – 26 TGF-β signaling is reported to facilitate tumor growth and metastasis in advanced cancer, and blocking TGF-β/ALK/Smad signaling could suppress the process of epithelial-to-mesenchymal transition. 27 Geng et al 28 demonstrated that downregulation of PPM1A expression could promote invasion and epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway.…”

TRIP suppresses cell proliferation and invasion in choroidal melanoma via promoting the proteasomal degradation of Twist1

“…4C). Given that Twist1 can be induced by TGF‐β [22], we additionally explore the interaction between endogenous Twist1 and TRIP in TGF‐β‐stimulated M619 cells via IP using antibodies specific for Twist1 or TRIP (Fig. 4D,E).…”

Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models

“…Through RNA-seq analysis, the DEGs related to TGF-β signalling were identified in response to combination treatment of vactosertib with nal-IRI/5-FU/LV. For example, BCL9L and SNCG are involved in TGF-β-induced EMT, migration, invasion, and metastasis 32,33 . The expression of BCL9L is up-regulated in pancreatic cancer 34 , and knockdown of BCL9L diminishes TGF-β-induced EMT responses in pancreatic cancer cells and inhibits liver metastasis in vivo 32 .…”

“…The expression of SNCG is up-regulated in breast, colon, and pancreatic cancers [35][36][37] . SNCG is involved in perineural invasion associated with local recurrence and dismal prognosis in relation with TGF-β or Twist in pancreatic cancer 33 . In this study, we found that combination treatment of vactosertib with nal-IRI/5-FU/LV significantly reduced SNCG and BCL9L expression.…”