ZHAOHUI WU, M.D., Ph.D.

Associate Professor
Pathology

Office: 118 Cancer Research Building
19 South Manassas
Memphis Tn 381033403
Tel: (901) 448-2612
zwu6@uthsc.edu
http://www.uthsc.edu/cancer/researchteam.php

Education

  • 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, therapeutic resistance, metastasis, miRNA

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.

A long-standing interest of my laboratory is to understand cellular responses to genotoxic stress and their pathophysiological functions in human health and disease. We mainly focus on two directions: 1) cancer cell responses to genotoxic treatments, such as radiation therapy and cytotoxic chemotherapy, and their roles in mediating therapeutic response and metastasis; 2) cellular stress response to environmental genotoxic exposure, such as UV radiation and genotoxic chemicals, and their functions in cancer initiation and anti-tumor immune surveillance.

Cancer cell responses to genotoxic treatments

We are particularly interested in the molecular mechanisms and pathological function of a family of transcription factors, termed Nuclear Factor kappa B (NF-kB), in DNA damage response of cancer cells. NF-kB activation is an important component of cellular response to genotoxic stress, and it can be activated by cytotoxic agents used in cancer therapy. 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, of either epithelial or hematopoietic origin, 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 previous studies revealed an atypical genotoxic NF-kB signaling cascade which depends on ATM activation and sequential modification of NEMO. (Huang et al, Cell 2003; Wu et al. Science 2006) We found that ATM directly interacts and phosphorylates NEMO, which is critical for subsequent NEMO ubiquitination and nuclear exportation. Further, our evidence suggests that ATM is also exported with NEMO and plays an important role in activating the IKK complex in the cytoplasm. Our recent studies showed that a variety of ubiquitination events play critical roles in regulating this atypical NF-kB signaling pathway. We found ELKS is modified by K63-linked polyubiquitin chain in an ATM-dependent manner (Wu et al. Mol Cell 2010), whereas nuclear exported NEMO was attached with linear polyubiquitin chain (Niu et al. EMBO J 2011). Both chain-specific ubiquitination events were required for optimal NF-kB activation in cancer cells exposed to genotoxic agents. Lately, we also uncovered a negative-feedback response of genotoxic NF-kB signaling involving MCPIP1 induction and USP10-mediated deubiquitination of NEMO and ELKS (Niu et al. EMBO J 2013). Currently, we are further investigating this negative regulatory mechanism and examine its significance and potential application in sensitizing cancer cells to genotoxic treatments. Meanwhile, we recently generated a conditional knockout mouse model which is being used to further interrogate the pathological function of genotoxic NF-kB signaling cascade in modulating cancer cell response to radiation and chemotherapeutic drugs.

Our recent studies have also revealed another critical pathological function of genotoxic NF-kB signaling in cancer progression. In triple-negative breast cancer (TNBC) patients, although they initially are more sensitive to chemotherapy compared with other subtypes of breast cancer, TNBC patients rapidly develop resistance to the treatment, which leads to a high incidence of early relapse within 2-3 years of diagnosis. Moreover, TNBC is characterized by aggressive invasion and unique pattern of metastases, which may further contribute to the rapidly arising resistance developed in TNBC patients. We found chemotherapy-induced genotoxic NF-kB activation may modulate both acquired therapeutic resistance and aggressive metastasis in TNBC. Through expression profiling in TNBC cells, we identified a list of microRNAs whose expression is controlled by genotoxic NF-kB signaling. We showed that Doxorubicin-induced NF-kB activation and subsequent IL6-STAT3 signaling collaboratively upregulated miR-21 expression in TNBC cells. The increased miR-21 promoted both cell survival and aggressive invasion of TNBC cells in response to genotoxic treatment (Niu et al. JBC 2012). Moreover, the similar miRNA induction by genotoxic NF-kB activation was also observed in skin cancer cells, which regulated apoptotic response to UV radiation (Tan et al. JBC 2012). We are further characterizing additional DNA damage-induced miRNAs which may play critical roles in promoting TNBC metastasis and therapeutic resistance.

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.

Cellular stress response to environmental genotoxic exposure

We are also investigating the NF-kB activation by environmental genotoxic exposure and its function in regulating the balance between oncogenesis and anti-tumor immune response. We found in response to UV radiation, NF-kB can be activated in skin cells. In commonly used experimental UVR models, UVC-induced NF-kB signaling is consistent with the atypical genotoxic NF-kB signaling we described (Wu et al. EMBO J 2008; Tan et al. JBC 2012). However, within the solar UV spectrum, UVB and UVA are of major environmental significance to skin carcinogenesis since most UVC is absorbed by ozone in the earth''s atmosphere. UVB can penetrate into dermis papillary area and effectively induce DNA damage in residing skin keratinocytes, melanocytes and dendritic cells, resulting in its much higher carcinogenicity than UVA. Unexpectedly, we found NF-kB activation by UVB radiation was mediated by a distinct NF-kB signaling cascade which has not been characterized. We are currently further exploring the molecular signaling cascade mediating this novel NF-kB activation pathway in response to UVB. In addition, we found UVB-induced NF-kB activation is essential for mediating melanoma cell susceptibility to innate anti-tumor surveillance by inducing “damage” cell markers. Our ongoing investigation aims to reveal how UVB-induced NF-kB activation orchestrates skin cell stress response which may activate NK cell-dependent innate immunity to eliminate transformed cells at the precancerous stage as well as antagonize skin cancer progression. Since aberrant NF-kB activation has been implicated in initiation of skin cancers, how pathophysiological outcomes of NF-kB activation are coordinated between its pro- and anti-tumorigenic functions also warrants further investigation.

Publications

  1. Niu, J, Xue, A, Chi, Y, Xue, J, Wang, W, Zhao, Z, Fan, M, Yang, CH, Shao, ZM, Pfeffer, LM, Wu, J, Wu, ZH. Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. Oncogene, 2015.
  2. Wang, W, Huang, X, Xin, HB, Fu, M, Xue, A, Wu, ZH. TRAF Family Member-Associated NF-κB Activator Inhibits Genotoxic NF-κB Activation by Facilitating USP10-Dependent Deubiquitination of TRAF6. J Biol Chem, 2015.
  3. Xue, J, Chi, Y, Chen, Y, Huang, S, Ye, X, Niu, J, Wang, W, Pfeffer, LM, Shao, ZM, Wu, ZH, Wu, J. MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity. Oncogene, 2015.
  4. Xue, J, Niu, J, Wu, J, Wu, ZH. MicroRNAs in cancer therapeutic response: Friend and foe. World J Clin Oncol, 5 (4), 730-43, 2014.
  5. 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.
  6. 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.
  7. Wu, ZH, Shi, Y. When Ubiquitin Meets NF-κB: A trove for anti-cancer drug development. Curr Pharm Des, 2012.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Simonson, SJ, Wu, ZH, Miyamoto, S. CYLD: a DUB with many talents. Dev Cell, 13 (5), 601-3, 2007.
  18. Wu, ZH, Miyamoto, S. Many faces of NF-kappaB signaling induced by genotoxic stress. J Mol Med, 85 (11), 1187-202, 2007.
  19. 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.
  20. 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.
  21. Wu, ZH, Mabb, A, Miyamoto, S. PIDD: a switch hitter. Cell, 123 (6), 980-2, 2005.
  22. 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.
  23. 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.
  24. 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.
  25. 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.