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// Ji-Lian Wang 1 , Zhen Qi 2 , Ye-Hua Li 2 , Hong-Mei Zhao 1 , Ye-Guang Chen 2 and Wei Fu 1 1 Department of General Surgery, Peking University Third Hospital, Beijing 100191, China 2 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China Correspondence to: Wei Fu, email: fuwei@bjmu.edu.cn Keywords: colorectal cancer, TGIF1, Wnt signaling, β-catenin, TGF-β Received: March 24, 2017 Accepted: June 20, 2017 Published: July 26, 2017 ABSTRACT Colorectal cancer (CRC) is one of the most common cancers, but the mechanisms underlying its initiation and progression are largely unknown. TGIF1 (TGFB induced factor homeobox 1) is a transcriptional corepressor that belongs to the three-amino acid loop extension (TALE) superclass of atypical homeodomains. It has been reported that TGIF1 is highly expressed in mammary cancer and non-small cell lung cancer and can enhance tumor progression. However, the role of TGIF1 in colorectal cancer remains unknown. Here, we report that TGIF1 is significantly upregulated in colorectal cancers, and its high expression predicts poor prognosis. Overexpression of TGIF1 markedly promotes the proliferation of colorectal cancer cells both in vivo and in vitro . In addition, TGIF1 activates Wnt/β-catenin signaling, and the homeodomain is indispensable for Wnt activation and β-catenin interaction. Taken together, our results suggest that TGIF1 is a novel colorectal tumor promoter and indicate that TGIF1 enhances colorectal cancer tumorigenesis through activating Wnt signaling.

// Yeon-Jin Kwon 1 , Boris A. Leibovitch 1 , Nidhi Bansal 1 , Lutecia Pereira 2 , Chi-Yeh Chung 1 , Edgardo V. Ariztia 1 , Arthur Zelent 2 , Eduardo F. Farias 1 and Samuel Waxman 1 1 Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, USA 2 University of Miami, Sylvester Comprehensive Cancer Center, Florida MI, USA Correspondence to: Samuel Waxman, email: samuel.waxman@mssm.edu Eduardo F. Farias, email: eduardo.farias@mssm.edu Keywords: triple negative breast cancer, invasion, SIN3A, TGIF1, Wnt, metastasis Received: May 20, 2016 Accepted: July 23, 2016 Published: August 19, 2016 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.