Postdoctoral Fellowship, Harvard Medical School
Ph.D. Purdue University, 1997
B.S., Nankai University
The Wnt/ß-catenin signaling pathway plays important roles in early development, stem cell renewal, and tumorigenesis. In addition, Wnt signaling is crucial in the organization and maintenance of the human intestinal epithelium. In this pathway, many different components work together to transduce an external signal into changes in gene expression within the target cell. Upon binding its receptor, the Wnt ligand ultimately results in the stabilization of cytoplasmic ß-catenin, which is then free to enter the nucleus and activate transcription through its interaction with the TCF/LEF family of transcription factors.
Somatic mutations that result in deregulated Wnt signaling are an early event in the development of colorectal cancer, which is the second leading cause of cancer death in the United States. About 80% of colorectal cancers have APC (adenomatous polyposis coli) mutation, and about 15% have ß-catenin mutation. We have identified novel molecules in the Wnt pathways, and have provided insights into how mutations cause ß-catenin accumulation that leads to cancer.
We are also interested in the crosstalk between Wnt signaling and other signaling pathways. We have identified KLF4 as a novel inhibitor of ß-catenin. KLF4 is a tumor suppressor and a key factor for stem cell re-programming. We found that KLF4 controls transcription by regulating chromatin-remodeling. We are currently investigating the molecular mechanisms of KLF4 in cancers and in iPS cells (induced pluripotent stem cells).
We are collaborating with clinicians in the Markey Cancer Center to study Wnt/ß-catenin signaling in human cancers, especially GI cancers. We are collaborating with chemists at UK and Biotech companies to develop ß-catenin inhibitors. Our long-term goal is to investigate the molecular mechanisms of human cancers, including cancer stem cells, and to use our knowledge of cell signaling to develop novel therapeutics and diagnostics for GI cancers.
1. Liu C, Kato Y, Zhang Z, Do VM, Yankner BA and He X. beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc. Natl. Acad. of Sci. USA 96: 6273-6278, 1999.
2. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X. LDL-receptor-related proteins in Wnt signal transduction. Nature 407: 530-535, 2000.
3. Liu C, Li Y, Semenov M, Han C, Baeg G, Tan Y, Zhang Z, Lin X, He X. Control of beta-catenin phosphorylaton/degradation by a dual-kinase mechanism. Cell 108: 837-847, 2002.
4. Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z, and He X. A mechanism for Wnt co-receptor activation. Molecular Cell 13:149-156, 2004.
5. Shao J, Jung C, Liu C and Sheng H. Prostaglandin E2 stimulates the beta-catenin/TCF-dependent transcription in colon cancer. J Biol Chem 280: 26565-26572, 2005.
6. Evans PM, Liu C. SiteFind: A software tool for introducing a restriction site as a marker for successful site-directed mutagenesis. BMC Molecular Biology 6:22, 2005.
7. Zhang W, Chen X, Kato Y, Evans PM, Yuan S, Yang J, Rychahou PG, Yang VW, He X, Evers BM and Liu C. Novel crosstalk of Krüppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression. Molecular and Cellular Biology 26: 2055-2064, 2006.
8. Yang J, Zhang W, Evans PM, Chen X, He X and Liu C. APC differentially regulates beta-catenin phosphorylation and ubiquitination in colon cancer cells. J Biol Chem 281:17751-17757, 2006.
9. Zhang B, Luo S, Dong XP, Zhang X, Liu C, Luo Z, Xiong WC and Mei L. Beta-catenin regulates AChR clustering in muscle cells through interaction with rapsyn. Journal of Neuroscience 27: 3968-3973, 2007.
10. Evans PM, Zhang W, Chen X, Yang J, Bhakat K and Liu C. Krüppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation. J Biol Chem 282: 33994-4002, 2007.
11. Zheng H, Pritchard DM, Yang X, Bennett E, Liu G, Liu C and Ai W. KLF4 gene expression is inhibited by the Notch signaling pathway that controls goblet cell differentiation in mouse GI tract. Am J Physiol Gastrointest Liver Physiol 296: G490-82008, 2009.
12. Song S, Mazurek N, Liu C, Sun Y, Ding QQ, Liu K, Hung MC, Bresalier RS. Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of GSK-3beta activity. Cancer Research 69: 1343-9, 2009.
13. Zhang W, Yang J, Liu Y, Chen X, Yu T, Jia J and Liu C. PR55alpha, a regulatory subunit of PP2A, specifically regulates PP2A-mediated beta-catenin dephosphorylation. J Biol Chem, 284: 22649-22656, 2009.
14. Zong W, Yang Y, Zhang P, Andrianakos R, Hasegawa K, Lyu J, Chen X, Bai G, Liu C, Pera M and Lu W. Klf4 directly interacts with Oct4 and Sox2 to promote reprogramming. Stem Cells 15: 2969-2978, 2009.
16. Evans PM, Chen X, Zhang W and Liu C. KLF4 interacts with beta-catenin/TCF4 and blocks recruitment of p300/CBP by beta-catenin. Mol Cell Biol. 30: 372-381, 2010.
17. Zhang P, Andrianakos R, Yang, Liu C and Lu W. Krüppel-like factor 4 (KLF4) prevents embryonic stem (ES) cell differentiation by regulation Nanog gene expression. J Biol Chem, 285, 9180-9189, 2010.
18. Wang J, Liu B, Wang N, Lee YM, Liu C, and Li K. TRIM56 Is a Virus- and Interferon-Inducible E3 Ubiquitin Ligase That Restricts Pestivirus Infection. Journal of Virology, 85: 3733-3745, 2011.
19. Zhang W, Sviripa V, Kril LM, Chen X, Yu T, Shi J, Rychahou P, Evers BM, Watt DS, and Liu C. Fluorinated N,N-Dialkylaminostilbenes for Wnt Pathway Inhibition and Colon Cancer Repression. J Med Chem, 54: 1288–1297, 2011.
20. Yu T, Chen X, Zhang W, Colon D, Shi J, Napier D, Rychahou P, Lu W, Lee EY, Evers BM and Liu C. Regulation of the Potential Marker for Intestinal Cells, Bmi1, by beta-Catenin and the Zinc Finger Protein KLF4: Implications for Colon Cancer. J Biol Chem, 287: 3760-8, 2012.
21. Olivier S, Guinez C, Mir AM, Perez-Cervera Y, Liu C, Michalski JC and Lefebvre T. The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of β-catenin and cell proliferation. Am J Physiol Endocrinol Metab. 302: E417-24, 2012.
22. Yu T, Chen X, Zhang W, Li J, Xu R, Wang TC, Ai W and Liu C. Krüppel-like factor 4 regulates intestinal epithelial cell morphology and polarity. PloS One, 7: e32492, 2012.
23. Li J, Zheng H, Yu F, Yu T, Liu C, Huang S, Wang T and Ai W. Deficiency of the Krüppel-like factor KLF4 correlates with increased cell proliferation, migration, adhesion, and enhanced skin tumorigenesis. Carcinogenesis 33: 1239-46, 2012.
24. Lin HS, Sviripa VM, Watt DS, Liu C, Xiang TX, Anderson BD, Ong PS, Ho PC. Quantification of trans-2,6-difluoro-4′-N,N-dimethylaminostilbene in rat plasma: Application to a pharmacokinetic study. Journal of Pharmaceutical and Biomedical Analysis. 72: 115-120, 2013.
25. Kim JT, Li J, Jang ER, Gulhati P, Rychahou PG, Napier DL, Wang C, Weiss HL, Lee EY, Anthony L, Townsend CM Jr, Liu C, Evers BM. Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors. Carcinogenesis, Epub ahead of print, 2013.
26. Sviripa VM, Zhang W, Conroy MD, Schmidt ES, Liu AX, Truong J, Liu C, Watt DS. Fluorinated
N,N'-Diarylureas as AMPK Activators. Bioorganic & Medicinal Chemistry Letters, Epub ahead of print, 2013.
27. Zhang W, Sviripa VM, Chen X, Shi J, Yu T, Hamza A, Ward N, Kril L, Vander Kooi C, Zhan C, Evers, BM, Watt DS and Liu C. Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. ACS Chemical Biology, Epub ahead of print, 2013.