Inhibition of Cancer Cell Migration and Invasion through Suppressing the Wnt1-mediating Signal Pathway by G-quadruplex Structure Stabilizers

• Published in: The Journal of biological chemistry Vol. 289; no. 21; pp. 14612 - 14623
• Main Authors: Wang, Jing-Ming, Huang, Fong-Chun, Kuo, Margaret Hsin-Jui, Wang, Zi-Fu, Tseng, Ting-Yuan, Chang, Lien-Cheng, Yen, Shao-Jung, Chang, Ta-Chau, Lin, Jing-Jer
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Anticancer Drug; beta Catenin - metabolism; Carbazoles - pharmacology; Cell Line, Tumor; Cell Migration; Cell Movement - drug effects; DNA Structure; G-quadruplex; G-Quadruplexes - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Gene Regulation; Humans; Immunoblotting; Inhibitor of Apoptosis Proteins - genetics; Matrix Metalloproteinase 7 - genetics; Neoplasm Invasiveness; Oligonucleotides - chemistry; Oligonucleotides - genetics; Promoter Regions, Genetic - genetics; Promoters; Pyrazines - pharmacology; Pyridinium Compounds - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Signal Transduction - genetics; Survivin; Wnt Pathway; Wnt1 Protein - genetics; Cell Migration; Wnt Pathway; DNA Structure; Anticancer Drug; Promoters; G-quadruplex
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.548230

WNT1 encodes a multifunctional signaling glycoprotein that is highly expressed in several malignant tumors. Patients with Wnt1-positive cancer are usually related to advanced metastasis. Here, we found that a stretch of G-rich sequences located at the WNT1 promoter region is capable of forming G-quadruplex structures. The addition of G-quadruplex structure stabilizers, BMVC and BMVC4, raises the melting temperature of the oligonucleotide formed by the WNT1 promoter G-rich sequences. Significantly, the expression of WNT1 was repressed by BMVC or BMVC4 in a G-quadruplex-dependent manner, suggesting that they can be used to modulate WNT1 expression. The role of G-quadruplex stabilizers on Wnt1-mediated cancer migration and invasion was further analyzed. The protein levels of β-catenin, a mediator of the Wnt-mediated signaling pathway, and the downstream targets MMP7 and survivin were down-regulated upon BMVC or BMVC4 treatments. Moreover, the migration and invasion activities of cancer cells were inhibited by BMVC and BMVC4, and the inhibitory effects can be reversed by WNT1-overexpression. Thus the Wnt1 expression and its downstream signaling pathways can be regulated through the G-quadruplex sequences located at its promoter region. These findings provide a novel approach for future drug development to inhibit migration and invasion of cancer cells. The Wnt1 pathway is recognized to play a major role in cancer progression. The promoter region of the WNT1 gene can form G-quadruplex structures, which regulate WNT1 expression and its downstream signaling pathways. The Wnt1-mediated migration and invasion activities of cancer cells are inhibited by G-quadruplex stabilizers. A pathway-specific strategy is identified to repress cancer metastasis using G-quadruplex stabilizers.