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.
Highlights
Gamma-synuclein (SNCG) is one of the three members of the synuclein family (α-synuclein/SNCA, β-synuclein/ SNCB, and SNCG), which are preferentially expressed in the brain and peripheral nervous system
Similar effects were detected in HeLa cells transfected with or without Twist[1] and SNCG small interfering RNA (siRNA) (Fig. 6b)
TGFβ1 expression in invasive cancer correlates with markers of tumor progression, such as metastasis, extracellular matrix (ECM) deposition, and the infiltration of immune suppressive cells
Summary
Gamma-synuclein (SNCG) is one of the three members of the synuclein family (α-synuclein/SNCA, β-synuclein/ SNCB, and SNCG), which are preferentially expressed in the brain and peripheral nervous system. While the biophysical properties of native SNCA remains controversial[3,4], SNCA is Normally, SNCG is expressed in peripheral neurons, ocular tissue, and adipose[8,9]. SNCG is overexpressed in various types of human tumors, such as breast, ovary, colon, liver, and cervical cancer[10,11,12,13]. Overexpression of SNCG in cancer cells may be due to aberrant demethylation of CpG islands within the promoter, AP1 transactivation, and insulin-like growth factor signaling[13,14,15]. SNCG promotes cancer metastasis and cancer cell survival under stresses[16,17,18,19]. The stability or activity of multiple kinases, such as IGF-1R, Akt, and ERK1/2, is enhanced by SNCG14,19,21
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