Assistant Professor

Office: 118 Cancer Research Building
Tel: (901) 448-2612


  • PostDoc, University of Wisconsin-Madison
  • Ph.D., Fudan University, Shanghai, P.R. China
  • M.D., Shanghai Medical University, Shanghai, P.R. China

Research interest/specialty

DNA damage response, Gene transcription, signaling transduction

Research Description

Genomic instability is a fundamental hallmark of oncogenesis. To maintain stable genome, cells evolved complex DNA-damage response (DDR), such as cell-cycle arrest, DNA repair and cell death. These mechanisms and pathways are also exploited by other physiological functions such as creating genetic diversity during development of immune cells. The research of DDR pathways has implication for elucidating the mechanisms that control cancer development and immune cell maturation, as well as ultimately for devising anti-cancer therapeutic approaches.

We are interested in the molecular mechanisms and biological function of a family of transcription factors, termed Nuclear Factor kappaB (NF-kB), in cellular DDR. NF-kB signaling is a prime component of DDR, and it can be activated by genotoxic agents used in cancer treatment, such as ionized radiation and chemotherapeutic drugs. NF-kB has been intensively studied for its function in regulating immune response, inflammation, as well as its significant correlation with cancer development. Regardless of the mechanisms, many cancer cells use NF-kB to achieve resistance to therapeutic agents. Modulating NF-kB activation has emerged as a promising strategy to enhance the efficacy of cancer treatment. Our current research focus includes:

To explore the molecular mechanism of genotoxic NF-kB signaling: DNA double strand breaks (DSB) induce activation of a nuclear phosphoinositide-3 kinase related kinase ATM. We found that DSB also induce the SUMOylation of the regulatory subunit of IKK complex, NF-kB Essential Modulator (NEMO/IKKg), which facilitates NEMO nuclear accumulation. Both NEMO and ATM are essential for NF-kB activation by genotoxic agents. ATM directly interacts and phosphorylates NEMO, which is critical for subsequent NEMO ubiquitination and nuclear exportation. Further, our data suggest that ATM may also be exported with NEMO and plays an important role in activating the IKK complex in the cytoplasm. We have recently shown that multiple forms of post-translational modification coordinate for effective genotoxic NF-kB activation. We will employ biochemical, molecular and cell biological approaches along with novel transgenic mouse models to further delineate this signaling pathway.

To define ‘NF-kB-response signatures’ of different cancer in response to various genotoxic agents: NF-kB is conventionally considered as anti-apoptotic transcription factor by activating anti-apoptotic gene expression, such as Bcl-XL, FLIP and cIAPs, which is believed to be one of the major mechanisms involved in tumor therapeutic resistance. However, NF-kB can also activate pro-apoptotic gene transcription, such as Death Receptors, Fas-Ligand and P53, along with repression of certain anti-apoptotic genes. We found that NF-kB activation may promote cell death in response to selective chemodrugs in several cancer cell lines. The contradictory biological outcomes of the NF-kB activation in response to different chemodrugs are governed by differential gene expression profiles orchestrated by NF-kB and other co-regulators. We are interested to analyze the specific pool of NF-kB responsive genes and cluster ‘NF-kB-response signatures’ in tumor cells upon treatment with different DNA-damaging anti-cancer agents. Profiling the radio/chemotherapy-responsive gene expression in different cancer settings could identify possible biomarkers to predict prognosis, and personalize cancer treatment. The further investigation on the underlying mechanisms dictating the DNA damage-induced expression of specific gene clusters will empower us to reprogram the therapeutic responses in tumor cells to achieve a better prognosis.

Other research area we are also interested includes DDR and genotoxic NF-kB signaling in tumor immune surveillance, DNA damage-modulated miRNA function, potential cytoplasmic function of ATM, crosstalk between NF-kB and other gene transcription regulators, etc. Ultimately the knowledge gained from these studies will help us to reduce tumor incidence and improve the efficacy of cancer treatment.


  1. Niu, J, Shi, Y, Xue, J, Miao, R, Huang, S, Wang, T, Wu, J, Fu, M, Wu, ZH. USP10 inhibits genotoxic NF-κB activation by MCPIP1-facilitated deubiquitination of NEMO. EMBO J, 32 (24), 3206-19, 2013.
  2. Fan, M, Krutilina, R, Sun, J, Sethuraman, A, Yang, CH, Wu, ZH, Yue, J, Pfeffer, LM. Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells. J Biol Chem, 288 (38), 27480-93, 2013.
  3. Wu, ZH, Shi, Y. When Ubiquitin Meets NF-κB: A trove for anti-cancer drug development. Curr Pharm Des, 2012.
  4. Tan, G, Niu, J, Shi, Y, Ouyang, H, Wu, ZH. NF-κB-dependent microRNA-125b upregulation promotes cell survival by targeting p38α upon UV radiation. J Biol Chem, 2012.
  5. Niu, J, Shi, Y, Tan, G, Yang, CH, Fan, M, Pfeffer, LM, Wu, ZH. DNA damage induces NF-κB-dependent microRNA-21 upregulation and promotes breast cancer cell invasion. J Biol Chem, 2012.
  6. Tan, G, Shi, Y, Wu, ZH. MicroRNA-22 promotes cell survival upon UV radiation by repressing PTEN. Biochem Biophys Res Commun, 417 (1), 546-51, 2012.
  7. Choudhary, S, Rosenblatt, KP, Fang, L, Tian, B, Wu, ZH, Brasier, AR. High throughput siRNA screening of the human kinome identifies novel kinases controlling the canonical NF-kB activation pathway. J Biol Chem, 2011.
  8. Martin, SE, Wu, ZH, Gehlhaus, K, Jones, TL, Zhang, YW, Guha, R, Miyamoto, S, Pommier, Y, Caplen, NJ. RNAi Screening Identifies TAK1 as a Potential Target for the Enhanced Efficacy of Topoisomerase Inhibitors. Curr Cancer Drug Targets, 2011.
  9. Niu, J, Shi, Y, Iwai, K, Wu, ZH. LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. EMBO J, 2011.
  10. Wu, ZH, Wong, ET, Shi, Y, Niu, J, Chen, Z, Miyamoto, S, Tergaonkar, V. ATM- and NEMO-Dependent ELKS Ubiquitination Coordinates TAK1-Mediated IKK Activation in Response to Genotoxic Stress. Mol Cell, 40 (1), 75-86, 2010.
  11. Wu, ZH, Miyamoto, S. Induction of a pro-apoptotic ATM-NF-kappaB pathway and its repression by ATR in response to replication stress. EMBO J, 27 (14), 1963-73, 2008.
  12. Ni, CY, Wu, ZH, Florence, WC, Parekh, VV, Arrate, MP, Pierce, S, Schweitzer, B, Van Kaer, L, Joyce, S, Miyamoto, S, Ballard, DW, Oltz, EM. Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo. J Immunol, 180 (11), 7107-11, 2008.
  13. Simonson, SJ, Wu, ZH, Miyamoto, S. CYLD: a DUB with many talents. Dev Cell, 13 (5), 601-3, 2007.
  14. Wu, ZH, Miyamoto, S. Many faces of NF-kappaB signaling induced by genotoxic stress. J Mol Med, 85 (11), 1187-202, 2007.
  15. Berchtold, CM, Wu, ZH, Huang, TT, Miyamoto, S. Calcium-dependent regulation of NEMO nuclear export in response to genotoxic stimuli. Mol Cell Biol, 27 (2), 497-509, 2007.
  16. Wu, ZH, Shi, Y, Tibbetts, RS, Miyamoto, S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science, 311 (5764), 1141-6, 2006.
  17. Wu, ZH, Mabb, A, Miyamoto, S. PIDD: a switch hitter. Cell, 123 (6), 980-2, 2005.
  18. Huang, TT, Wuerzberger-Davis, SM, Wu, ZH, Miyamoto, S. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell, 115 (5), 565-76, 2003.
  19. Englander, EW, Hu, Z, Sharma, A, Lee, HM, Wu, ZH, Greeley, GH. Rat MYH, a glycosylase for repair of oxidatively damaged DNA, has brain-specific isoforms that localize to neuronal mitochondria. J Neurochem, 83 (6), 1471-80, 2002.
  20. Jin, HM, Liu, QH, Cao, X, Wu, ZH, Zhang, GP, Zhang, M, Sha, ZY. Dysfunction of microvascular endothelial cells induced by tumor necrosis factor (TNFalpha): cellular and molecular mechanism. Clin Hemorheol Microcirc, 23 (2-4), 109-12, 2001.
  21. Jin, H, Wu, Z, Tian, T, Gu, Y. Apoptosis in atrophic skeletal muscle induced by brachial plexus injury in rats. J Trauma, 50 (1), 31-5, 2001.