Targeted interference of SIN3A-TGIF1 function by SID decoy treatment inhibits Wnt signaling and invasion in triple negative breast cancer cells

Yeon Jin Kwon, Boris A. Leibovitch, Nidhi Bansal, Lutecia Pereira, Chi Yeh Chung, Edgardo V. Ariztia, Arthur Zelent, Eduardo F. Farias, Samuel Waxman

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Cancer cell invasion is an obligatory step for metastatic dissemination that contributes to rapid relapse and a poorer survival in triple negative breast cancer (TNBC) patients. Development of novel therapeutic strategies to block tumor invasion is an unmet need in the treatment of cancer. We reported that the selective inhibition of the PAH2 domain of SIN3A protein function markedly suppressed metastatic dissemination to the lungs in TNBC xenograft bearing mice. Here, we show that TNBC cell lines treated with Sin3 interaction domain (SID) decoy peptides that bind to PAH2 display a strong in vitro inhibition of transwell invasion. This is accompanied by actin cytoskeleton reorganization with increased cortical actin deposition and downregulation of known Wnt target genes that are associated with epithelial to mesenchymal transition (EMT) and cancer cell invasion. Wnt pathway inhibition by SID decoy peptide was confirmed by decreased Wnt reporter activity and altered cytoplasmic localization of nuclear β-catenin. TGIF1, a transcription factor that modulates Wnt signaling and known to interact with the PAH2 domain of SIN3A, can be dissociated from the SIN3A complex by SID decoys. TGIF1 knockdown inhibits WNT target genes and in vitro cell invasion suggesting that TGIF1 might be a key target of the SID decoys to block tumor invasion. Taken together, targeting SIN3 function using SID decoys is a novel strategy to reverse invasion and the EMT program in TNBC translating into the inhibition of metastasis dissemination and eradication of residual disease.

Original languageEnglish (US)
Pages (from-to)88421-88436
Number of pages16
JournalOncotarget
Volume8
Issue number51
DOIs
StatePublished - Jan 1 2017

Keywords

  • Invasion
  • Metastasis
  • SIN3A
  • TGIF1
  • Triple negative breast cancer
  • Wnt

ASJC Scopus subject areas

  • Oncology

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    Kwon, Y. J., Leibovitch, B. A., Bansal, N., Pereira, L., Chung, C. Y., Ariztia, E. V., Zelent, A., Farias, E. F., & Waxman, S. (2017). Targeted interference of SIN3A-TGIF1 function by SID decoy treatment inhibits Wnt signaling and invasion in triple negative breast cancer cells. Oncotarget, 8(51), 88421-88436. https://doi.org/10.18632/oncotarget.11381