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.

• Authors: Ting Shao, Peiying Song, Hui Hua, Hongying Zhang, Xiangmin Sun, Qingbin Kong, Jiao Wang, Ting Luo, Yangfu Jiang
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 6 Pg. 625 (05 24 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29795373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• Smad Proteins
• TWIST1 protein, human
• Transforming Growth Factor beta
• Twist-Related Protein 1
• gamma-Synuclein

Topics

• Cell Movement
• E-Box Elements
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Hep G2 Cells
• Humans
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Nuclear Proteins (metabolism)
• Promoter Regions, Genetic
• Smad Proteins (metabolism)
• Transforming Growth Factor beta (pharmacology)
• Twist-Related Protein 1 (metabolism)
• Up-Regulation (drug effects)
• gamma-Synuclein (genetics, metabolism)