Targeted interference of SIN3A-TGIF1 function by SID decoy treatment inhibits Wnt signaling and invasion in triple negative breast cancer cells
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Yeon-Jin Kwon1, Boris A. Leibovitch1, Nidhi Bansal1, Lutecia Pereira2, Chi-Yeh Chung1, Edgardo V. Ariztia1, Arthur Zelent2, Eduardo F. Farias1 and Samuel Waxman1
1Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, USA
2University of Miami, Sylvester Comprehensive Cancer Center, Florida MI, USA
Samuel Waxman, email: email@example.com
Eduardo F. Farias, email: firstname.lastname@example.org
Keywords: triple negative breast cancer, invasion, SIN3A, TGIF1, Wnt, metastasis
Received: May 20, 2016 Accepted: July 23, 2016 Published: August 19, 2016
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.
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