517 Med. Sci. Bldg.
Office: (217) 333-7764
Lab: (217) 333-7864
Fax: (217) 244-5858
Mail to: Department of Biochemistry
University of Illinois
600 S Mathews Ave
Urbana, IL 61801
Associate Professor of Biochemistry
Associate Professor of Medical Biochemistry at the College of Medicine
B.S. 1987 Xiamen University, China
M.S. 1990 Peking Union Medical University
Ph.D. 1999 Kyoto University, Japan
Postdoc. 1999-2003 Gladstone Institute of Immunology and Virology, University of California, San Francisco
Epigenetic regulation of NF-κB; the role of NF-κB in apoptosis and cancer; cross-talk between NF-κB and other signaling pathways. NF-κB signaling and H. pylori-mediated gastric disease. Function of RUNX3 as a tumor suppressor in cancer.
I. Epigenetic regulation of NF-κB; the role of NF-κB in apoptosis and cancer; cross-talk between NF-κB and other signaling pathways.
The eukaryotic transcription factor NF-κB regulates a wide range of host genes that govern the inflammatory and immune responses in mammals. The NF-κB signaling pathway controls multiple key cellular processes, including programmed cell death, cell proliferation, and differentiation. NF-κB is activated by a variety of chemokines, bacteria, viruses and their products via distinct signal transduction pathways mediated by different receptors, including TNF-α receptors, Toll-like receptors, and antigen-specific T- and B-cell receptors. The long-term goals of this laboratory are to determine how the NF-κB transcription factor complex is regulated at the molecular level and to elucidate the roles of NF-κB in inflammation, apoptosis, and tumorigenesis. In particular, we are interested in dissecting how different stimuli converge to activate NF-κB under normal and pathological conditions using a combination of biochemical, molecular, cellular, and genetic approaches.
Currently, we are interested in the role of post-translational modifications of NF-κB and histones in the regulation of NF-κB signaling pathway.
Post-translational modifications and NF-κB activation
While it is clear that post-translational modifications, including phosphorylation and acetylation, play critical roles in shaping the nuclear function of NF-κB, many unanswered questions remain. For example, how do these modifications regulate NF-κB in vivo? Do they contribute significantly to the NF-κBs proinflammatory or anti-apoptotic functions? Is there a "transcription factor code" generated by acetylation, phosphorylation, and other modifications? If so, does it mediate the selection of specific target genes or control the strength and duration of the nuclear action of NF-κB? Answering these questions would advance our understanding of how NF-κB is regulated and could also provide exciting new therapeutic options for manipulating NF-κB action in cancer or inflammation.
- Chromatin remodeling and NF-κB activation
To increase the accessibility of the cell’s transcription and replication machinery to promoters, chromatin remodeling must occur. For example, the conformation of chromatin is altered by chromatin remodeling complexes and the N-terminal tails of histones are modified by enzymes, including histone acetyltransferases and deacetylases, kinases, and methyl transferases. These enzymes play important roles in regulation of gene expression by modifying the histones and thus controlling the accessibility of chromatin by accessory regulator factors. Several of these enzymes interact with NF-κB and regulate NF-κB-dependent transactivation. However, it remains largely unknown whether and how chromatin remodeling mediates NF-κB target gene selection. How are these enzymes regulated in the NF-κB signaling pathway? Using different approaches including chromatin immunoprecipitation assays, we will identify the enzymes that are recruited to different NF-κB target genes in a stimulus-specific manner and determine how these recruitments are regulated.
II. NF-κB signaling and H. pylori-mediated gastric disease
Infection with Helicobacter pylori causes gastritis and peptic ulceration and is the strongest risk factor for the development of gastric cancer, the second leading cause of cancer-related death worldwide. The mechanisms involved in the bacterium’s ability to induce gastric cancer are believed to be linked to infection-associated chronic gastritis, which is characterized by increased expression of multiple inflammatory genes. Virulence factor CagA of H. pylori is critical for the infection-initiated inflammation. The transcription factor NF-κB plays a key role in regulating the immune and inflammatory response. Transcriptional activation of NF-κB relies on the proximal cytoplasmic events leading to the activation of IKKs and a series of nuclear events in which NF-κB is post-translationally modified. NF-κB is activated by H. pylori infection in a CagA-dependent manner and is responsible for H. pylori-associated gastritis. However, the mechanism by which H. pylori utilizes its CagA to activate NF-κB and to promote inflammation-associated gastritis and gastric cancer is not clear. Recently, we demonstrate that CagA physically associates with TAK1 (TGF-β activated kinase 1) and enhances the activity of TAK1 and TAK1-induced NF-κB activation via the TRAF6-mediated K63-linked ubiquitination of TAK1. These findings reveal that polyubiquitination of TAK1 regulates the activation of NF-κB and is utilized by H. pylori CagA for the H. pylori-induced inflammatory response.
III. Regulation and function of Brd4 in cancer and immunity
Brd4 has emerged as an important factor in regulating many biological processes, including cell cycle, inflammatory response, metabolism and tumorigenesis. We have recently identified bromodomain-containing factor Brd4 as a key regulator of NF-κB-mediated inflammatory response and cancer development. We have also demonstrated that small molecules inhibiting Brd4 possess strong anti-tumor and anti-inflammatory activities in cultured cells and in mouse models (Zou et al, Oncogene, 2014;Chen et al, J. Immunology, 2016). However, the regulation of Brd4 and its pathophysiological functions remain largely unknown. We are investigating on how Brd4 is regulated in cancer cells and how Brd4 regulates the innate immune response using Brd4 knockout animals. These studies will provide insights into the regulation of Brd4 and whether Brd4 represents a novel therapeutic target for the treatment of cancer and inflammtory diseases.
Hu XM, Dong SH, Chen J, Zhou XZ, Chen R, Lu KP, Chen LF. 2017. Prolyl isomerase Pin1 regulates the stability, transcriptional activity and oncogenic potential of Brd4. Oncogene [In press]
Bao Y, Wu XW, Chen JJ, Hu XM, Zeng FX, Cheng JJ, Jin H, Lin X and Chen LF. 2017. Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IκBα. Proc. Natl. Acad. Sci. U.S.A. [In press]
Chen JJ, Wang Z, Hu, XM, Chen R, Romero-Gallo J, Perk RM. and Chen LF. 2016. BET inhibition Attenuates H. pylori-induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation. J. Immunology 196:4132-42
Zou ZH, Huang B, Wu XW, Zhang HJ, Qi J, Bradner J, Nair S and Chen LF. 2014. Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene. 33:2395-404
Wu XW, Qi J, Bradner JE, Xiao GT and Chen LF. 2013. Bromodomain and extra-terminal (BET) protein inhibition suppresses HTLV-1 Tax-mediated tumorigenesis by inhibiting NF-κB signaling. J. Biol. Chem 288:36094-105
Tsang YH, Wu XW, Lin JS, Chee WO, Salto-Tellez M, Ito Y, Chen LF. 2012. Prolyl isomerase Pin1 down-regulates tumor suppressor RUNX3 in breast cancer. Oncogene 32:1488-96.
Chen LF. 2012. Tumor suppressor function of RUNX3 in breast cancer. J. of Cell Biochem. 113:1470-1477
Huang B, Qu ZX, Chee WO, Tsang YH, Xiao GT, Shapiro D, Salto-Tellez M, Ito K, Ito Y, Chen LF. 2011. RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α. Oncogene 31:527-34.
Huang B, Yang XD, Lamb A and Chen LF. 2010. Posttranslational modifications of NF-κB: another layer of regulation for NF-κB signaling pathway. Cellular Signaling. 22:1282-1290
Tsang YH, Lamb A, Romero-Gallo J, Huang B, Ito K, Peek RM, Ito Y and Chen LF. 2010. Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation. Oncogene 29:5643-50
Yang XD, Tajkhorshid E., Chen LF. 2010. "Functional interplay between acetylation and methylation of the RelA subunit of NF-κB." Mol. Cell. Biol. 30:2170-2180 [Abstract]
Lamb A, Yang XD, Tsang YH, Li JD, Higashi H, Hatakeyama M, Peek RM, Blanke SR, Chen LF. 2009. "Helicobacter pylori CagA activates NF-κB by inducing TRAF6-mediated K63-ubiquitination of TAK1." EMBO Report 10:1242-1249 [Abstract]
Yang XD, Lamb A, Chen LF. 2009. "Methylation, a new epigenetic mark for protein stability." Epigenetics. 4:429-33 [Abstract]
Yang XD, Huang B, Li MX, Lamb A, Kelleher NL, Chen LF. 2009. "Negative regulation of NF-κB action by Set9-mediated lysine methylation of RelA subunit." EMBO J. 28:1055-1066 [Abstract]
Huang B, Yang XD, Zhou MM, Ozato K, Chen LF. 2009. "Brd4 coactivates transcriptional activation of NF-κB via specific binding to acetylated RelA." Mol. Cell. Biol. 29(5):1375-87 [Abstract]
Ishinaga H., Jono H., Lim J.H., Kweon S.M., Xu H., Ha U.H., Xu H., Koga T., Yan C., Feng X.H., Chen L.F.*, Li J.D.*. 2007. "TGF-β induces p65 acetylation to enhance bacteria-induced NF-κB activation." EMBO J. 26:1150-1162 (*corresponding author). [Abstract]
Chen L.F.*, Williams S., Mu Y., Nakano H., Duerr J.M., Buckbinder L., and Greene W.C.*. 2005. "RelA phosphorylation regulates RelA acetylation." Mol. Cell. Biol. 25:7966-7975 (*corresponding author) [Abstract]
Chen, L.-F. and Greene, W.C. (2004) "Shaping the nuclear action of NF-κB," Nat. Rev. Mol. Cell. Biol. 5:302–401. [Abstract]
Chen, L.-F., Mu, Y., and Greene, W.C. (2002) "Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-κB," EMBO J. 21:6539–6548. [Abstract]
Chen, L.-F., Fischle, W., Verdin, E., and Greene, W.C. (2001) "Duration of nuclear NF-κB action regulated by reversible acetylation," Science 293:1653–1657. [Abstract]