Inhibition of cancer cell migration and invasion through suppressing the Wnt1-mediating signal pathway by G-quadruplex structure stabilizers.
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.
From the Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Jing-Ming
JM
Wang
Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Fong-Chun
FC
Huang
Institute of Atomic and Molecular Sciences, Academia Sinica, P. O. Box 23-166 Taipei, 106, Taiwan.
Margaret Hsin-Jui
MH
Kuo
Institute of Atomic and Molecular Sciences, Academia Sinica, P. O. Box 23-166 Taipei, 106, Taiwan, Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
Zi-Fu
ZF
Wang
Institute of Atomic and Molecular Sciences, Academia Sinica, P. O. Box 23-166 Taipei, 106, Taiwan, Institute of Biophotonics, National Yang-Ming University, Taipei 112, Taiwan, and.
Ting-Yuan
TY
Tseng
From the Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, Food and Drug Administration, Ministry of Health and Welfare, Taipei 115, Taiwan.
Lien-Cheng
LC
Chang
Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Shao-Jung
SJ
Yen
Institute of Atomic and Molecular Sciences, Academia Sinica, P. O. Box 23-166 Taipei, 106, Taiwan, Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, Institute of Biophotonics, National Yang-Ming University, Taipei 112, Taiwan, and tcchang@po.iams.sinica.edu.tw.
Ta-Chau
TC
Chang
From the Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan, jingjerlin@ntu.edu.tw.
Jing-Jer
JJ
Lin
D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D054856:G-Quadruplexes / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D009361:Neoplasm Invasiveness; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077022:Survivin; D051155:Wnt1 Protein / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
C486012:3,6-bis(1-methyl-4-vinylpyridium)carbazole diiodide; C577082:3,6-bis(4-methyl-2-vinylpyrazinium)carbazole; C107489:BIRC5 protein, human; D002227:Carbazoles; D051034:Inhibitor of Apoptosis Proteins; D009841:Oligonucleotides; D011719:Pyrazines; D011726:Pyridinium Compounds; D000077022:Survivin; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D051176:beta Catenin; D020783:Matrix Metalloproteinase 7
Anticancer Drug; Cell Migration; DNA Structure; G-quadruplex; Promoters; Wnt Pathway