Qing Zhang, PhD
The oxygen-sensing pathway contributes largely to the development of tumors. One of the central players in this pathway is prolyl hydroxylase (EglN1, 2 and 3). Our lab currently studies hypoxia signaling, prolyl hydroxylase and cancer, specifically breast and renal cell carcinoma.
One project focuses on using proteomic and genomic approaches to screen for novel prolyl hydroxylase substrates that play important roles in cancer. We have generated an IVT-compatible breast cancer gene library, which is comprised of 1200-1300 genes that were either reported or predicted to be important for breast tumorigenesis. Then, we developed a 96-well format high-throughput format to screen for whether any of the genes in the library can be hydroxylated in vitro by recombinant EglN2. Preliminary data from this screen identifies FOXO3a as one of potential EglN2 substrate. We are currently investigating the role of EglN2 target FOXO3a in breast cancer. In addition, we also developed an EglN2-substrate trapping strategy followed by TAP-TAG purification and mass spectrometry. Several potential EglN2 substrates have been identified from mass spectrometry and we are investigating their role in breast cancer as well.
The other project involves integrating CHIP-seq strategy with gene expression profiling in order to identify EglN2 prolyl hydroxylase and hypoxia inducible factor (HIF) targets in the malignant diseases. The ultimate goal is to understand mechanistically how oxygen-sensing pathways contribute to cancer progression, which will facilitate our design of efficient treatment strategies to specifically target cancer.
Zheng X, Zhai B, Koivunen P, Shin SJ, Lu G, Liu J, Geisen C, Chakraborty AA, Moslehi JJ, Smalley DM, Wei X, Chen X, Chen Z, Beres JM, Zhang J, Tsao JL, Brenner MC, Zhang Y, Fan C, Depinho RA, Paik JH, Gygi SP, Kaelin WG Jr* and Zhang Q*. Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes & Development, 2014 Jul 1;28(13):1429-44 (*:co-correspondent)
Lu G, Zhang Q, Huang Y, Song J, Tomaino R, Lim E, Liu W, Bronson RT, Bowman M, Dillon DA, Gygi SP, Mills GB, Richardson AL, Signoretti S, Yaffe MB, Kaelin WG. Phosphorylation of ETS1 by Src family kinase member prevents its recognition by the COP1 tumor suppressor. Cancer Cell, 2014, In press.
Chen X, Iliopoulos D*, Zhang Q*, Tang Q*, Greenblatt MB, Hatziapostolou M, Ni M, Chen Y, Lim E, Hu DZ, Hu B, Song M, Brown M, Liu XS, and Glimcher LH (2014). XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature, 2014 Apr 3;508 (7494):103-7. (*: equal contribution)
Zhang Q, Yang H. The roles of VHL-dependent ubiquitination in signaling and cancer. Frontiers in Oncology, 2012; 2:35.
Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X , Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang Q, Kulkarni RN, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya EV, Meyerson M, Kaelin WG Jr, Yan Q. Loss of the RBP2 histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proceedings of the National Academy of Sciences, 2011; 108(33): 13379-86.
Li Y, Zhang Q, Tian R, Wang Q, Zhao JJ, Iglehart JD, Wang ZC, Richardson AL. LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells. Cancer Research, 2011; 71(24): 7481-9.
Inuzuka H, Tseng A, Gao D, Zhai B, Zhang Q, Shaik S, Wan L, Ang X, Mock C, Yin H, Stommel JM, Gygi S, Lahav G, Asara J, Xiao Z, Kaelin WG, Harper JW and Wei W(2010). Phosphorylation by Casein Kinase I Promotesthe Turnover of the Mdm2 Oncoprotein via the SCFb-TRCP Ubiquitin Ligase. Cancer Cell, August 17; 18 (2): 147-59.
Zhang Q*, Gu J, Li L, Liu J, Luo B, Cheung HW, Boehm JS, Ni M, Geisen C, Root DE, Polyak K, Brown M, Richardson AL, Hahn WC, Kaelin WG, Bommi-Reddy A*(2009). Control of Cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydoxylase. Cancer Cell, Nov 3;16(5):413-24. (*: co-first author)
Nozawa H, Howell G, Suzuki S, Zhang Q, Qi Y, Klein-seetharaman J, Wells A, Grandis JR, Thomas SM (2008). Combined inhibition of PLCγ-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion. Clinical Cancer Research, Jul 1; 14 (13): 4336-4344.
Wang J, Singh N, Zhang Q, Lokshin A, Gooding WE, Shurin MR, Waes CV, Grandis JR, Hasegawa H, Ferris RL (2008). Autocrine chemokine receptor 7 (CCR7) activation in progression of squamous cell carcinoma of the head and neck (SCCHN). Journal of the National Cancer Institute, April 2; 100(7): 502-512.
Young AP, Schlisio S, Minamishima YA, Zhang Q, Li L, Grisanzio C, Signoretti S, Kaelin WG (2008). pVHL Loss Actuates a HIF-independent Senescence Program Mediated by pRb and p400. Nature Cell Biology, Mar 1; 10(3): 361-369.
Seethala RR, Gooding WE, Handler PN, Collins B, Zhang Q, Siegfried JM, Grandis JR (2008). Immunohistochemical analysis of phosphotyrosine STAT3 and EGFR autocrine signaling pathways in head and neck cancers & metastatic lymph nodes. Clinical Cancer Research, Mar 1; 14(5): 1303-1309.
Zhang Q, Bhola N, Lui VWY, Siwak DR, Xi S, Thomas SM, Ogagan MJ, Gubish CT, Siegfried JM, Mills GB, Grandis JR (2007). Anti-tumor mechanisms of combined GRPR and EGFR targeting in head and neck cancer. Molecular Cancer Therapeutics, Apr;6(4):1414-24.
Thomas SM, Bhola N, Zhang Q, Freilino M, Gooding WE, Siegfried JM, Chan DC, Grandis JR (2006). Crosstalk between G-protein-coupled receptor and EGFR signaling pathways contributes to growth and invasion of head and neck squamous cell carcinoma. Cancer Research, Dec 15; 66 (24): 11831-11839.
Zhang Q, Thomas SM, Lui VWY, Xi S, Siegfried JM, Fan H, Smithgall TE, Mills GB, Grandis JR (2006). Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation. Proceedings of the National Academy of Sciences, May 2: 103 (18): 6901-6906.
Xi S, Mark K, Dyer K, Zhang Q, Challet R, Ferris RA, Hunt J, Grandis JR (2006). Downregulation of STAT1 by promoter methylation is critical for squamous cell carcinogenesis. Journal of the National Cancer Institute, Feb 1: 98(3): 181-89.
Zhang Q, Thomas SM, Xi S, Smithgall TE, Siegfried JM, Kamens J, Gooding WE, Grandis JR (2004). Src family kinases mediate EGFR ligand cleavage, proliferation and invasion of cancer cells. Cancer Research, Sep 1; 64(17):6166-73.
Xi S, Zhang Q, Gooding WE, Smithgall TE, Grandis JR (2003). Constitutive activation of Stat5b contributes to carcinogenesis in Vivo. Cancer Research, 63 (20): 6763-6771.
Xi S, Zhang Q, Dyer KF, Lerner EC, Smithgall TE, Gooding WE, Kamens J, Grandis JR (2003). Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck. J. Biol.Chem. Vol 278 p31574-31583.
Lui VWY*, Thomas SM*, Zhang Q, Wentzel AL, Siegfried JM, Li JY, and Grandis JR (2003). The mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. Oncogene, 22(40): 6183-6193 (*: co-first author)