Hypoxia is associated with resistance towards radiation and chemotherapy. As tumors grow, they can sense the oxygen tension and reprogram critical pathways that are important for cancer cell survival and therapy resistance. One of examples is through upregulation of hypoxia inducible factor a (HIFa) and activation of HIF signaling downstream pathways. We are interested in studying the oxygen-sensing pathway and how they contribute to the development of tumors as well as therapeutic resistance. One of the central players in this pathway is prolyl hydroxylase (EglN1, 2 and 3), a family of iron- and 2-oxoglutarate-depedent dioxygenases. EglNs can hydroxylate HIFa on critical proline residues, which will trigger von Hippel-Lindau (VHL)-associated E3 ligase complex binding and lead to HIFa degradation. Our lab currently studies hypoxia, prolyl hydroxylase and VHL signaling in cancer, especially breast and renal cell carcinomas.
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 EglNs. For example, this screen identified FOXO3a as one of potential EglN2 substrates that regulates Cyclin D1 in breast cancer. Interestingly, FOXO3a protein stability regulation by prolyl hydroxylation is primarily mediated through USP9x deubiquitinase. 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 roles in breast cancer as well.
Another line of investigation has been focused on the role of EglN2 prolyl hydroxylase in regulating mitochondrial function in breast cancer. Our preliminary data showed that this regulation is independent of EglN2 enzymatic activity and EglN2 could potentially act as a transcriptional co-activator mediating critical gene expression involved in mitochondrial function. Our goal for this study is to elucidate the important pathway by which EglN2 controls mitochondrial function in breast cancer. 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.
In addition, our lab is also interested in identifying novel pVHL substrates in renal cancer. The VHL tumor suppressor gene was identified as a germline mutation in patients at risk for clear cell renal cell carcinoma (ccRCC), which accounts for approximately 85% of all renal cancers. More importantly, inactivating VHLmutations also play major roles in sporadic renal cell cancer. Loss of VHL-encoded protein (pVHL) function/expression leads to stabilization of a set of proteins (such as HIFs) regulating its downstream signaling, which have been found to contribute substantially to the transforming phenotype of renal cancer. It is critical to identify pathways that are affected by pVHL loss and that are key contributors to the overall renal cancer program, which will help design therapeutic invention strategies to target these drivers for renal cancer. We designed an innovative genome-wide in vitro expression strategy coupled with GST-binding screening and identified several interesting VHL binding proteins/substrates. We are currently validating their roles in renal carcinogenesis by using cancer cell lines, xenografts, mouse models and patient tissues.
Zhang J*, Wu T*, Simon J, Takada M, Saito R, Fan C, Liu X, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu XJ, Hu L, Wang J, Liao CH, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS and Zhang Q (2018). VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science, July 20; 361 (6399): 290-295. (*: equal contribution).
Zhang Q (2018). Correcting COMPASS Dysfunction in Cancer. Science Translational Medicine Vol.10, Issue 444, eaau0466.
Zhang Q (2018). RNase Moonlights as a Cancer Instigator. Science Translational Medicine Vol. 10, Issue 436, eaat3892.
Zhang J and Zhang Q (2018). Biomedicines. VHL and hypoxia signaling: beyond HIF in cancer. 2018 Mar 19;6(1). pii: E35. doi: 10.3390/biomedicines6010035. Review. PubMed PMID: 29562667.
Bryant JD, Brown MC, Dobrikov MI, Dobrikova EY, Gemberling SL, Zhang Q, Gromeier M. Regulation of HIF-1α during Hypoxia by DAP5-Induced Translation of PHD2. Mol Cell Biol. 2018 Mar 12. pii: MCB.00647-17. doi: 10.1128/MCB.00647-17. PubMed PMID: 29530922.
Zhang Q (2018) Stressing Myc Driven Cancer Out. Science Translational Medicine Vol. 10, Issue 428, eaar7535.
Wang L, Wrobel JA, Xie L, Li D, Zurlo G, Shen H, Yang P, Wang Z, Gunawardena HP, Zhang Q and Chen X (2018). Novel RNA-affinity proteogenomics dissects the interpatient tumor-phenotypic heterogeneity for revealing personalized markers for precision prognosis. Cell Chem Biol 2018 Feb 27. pii: S2451-9456(18)30038-2. doi: 10.1016/j.chembiol.2018.01.016. PubMed PMID: 29503206.
Zhang W, Karpen GH and Zhang Q (2017). Exploring the Role of CENP-A Ser18 Phosphorylation in CIN and tumorigenesis. Cell Cycle 2017 Oct 5:1-3. doi: 10.1080/15384101.2017.1387698. [Epub ahead of print] PubMed PMID: 28980868.
Takada M*, Zhang W*, Suzuki A, Kuroda T, Yu Z, Inuzuka H, Gao D, Wan L, Zhuang M, Hu L, Zhai B, Fry C, Bloom K, Li G, Karpen GH#, Wei W# and Zhang Q# (2017). FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/Cdk2-mediated phosphorylation of CENP-A. Cancer Research July 31st 2017 DOI: 1.1158/0008-5472. CAN-17-1240. PMID: 28760857.
Bailey ST, Smith AM, Kardos J, Wobker SE, Wilson HL, Krishnan B, Saito R, Lee HJ, Zhang J, Eaton SC, Williams LA, Peters DJ, Pan X, Felsher DW, Zhang Q, Parker JS, Yeh JJ, Moffitt RA, Leung JY and Kim WY (2017). Myc activation cooperates with Vhl and Ink4a/Arf loss to induce clear renal cell carcinoma. Nature Communication 2017 Jun 8;8:15770. doi: 10.1038/ncomms15770. PubMed PMID: 28593993.
Di Conza G, Cafarello ST, Zheng X, Zhang Q and Mazzone M (2017). PHD2 Targeting Overcomes Breast Cancer Cell Death Upon Glucose Starvation in a PP2A/B55a-Mediated Manner. Cell Reports, March 21st, Vol 18, 2836-2844. PMC5378984
Takada M*, Zhuang M*, Inuzuka H, Zhang J, Zurlo G, Zhang J and Zhang Q (2017). EglN2 Contributes to Triple Negative Breast Tumorigenesis By Functioning as a Substrate for the FBW7 Tumor Suppressor. Oncotarget 2017 Jan 24;8(4):6787-6795. doi: 10.18632/oncotarget.14290. (*: equal contribution) PMC5351669
Zurlo G, Guo J, Takada M, Wei W, Zhang Q. New Insights into Protein Hydroxylation and Its Important Role in Human Diseases. BBA-Reviews on Cancer, 2016 Sep 20. pii: S0304-419X(16)30065-8. doi: 10.1016/j.bbcan.2016.09.004.
Guo J, Chakraborty AA, Liu P, Gan W, Zheng X, Inuzuka H, Wang B, Zhang J, Zhang l, Yuan M, Novak J, Cheng JQ, Toker A, Signoretti S, Zhang Q, Asara JM, Kaelin WG JR, Wei W. pVHL suppresses kinase activity of Akt in a proline-hydroxylation dependent manner. Science, 2016 August 26; 353 (6302):929-932.
Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA, Patel H, Zhang Q, Signoretti S, Gerfen GJ, Richardson AL, Witkiewicz AK, Cravatt BF, Clardy J and Kaelin WG Jr. Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Cell 2016, Jun 30: 166 (1): 126-139.
Zhang J, Zheng X and Zhang Q (2015). EglN2 Positively Regulates Mitochondrial Function in Breast Cancer. Mol Cell Oncol. 2015 Dec 22;3(2):e1120845. doi: 10.1080/23723556.2015.1120845. eCollection 2016 Mar.
Zhang J*, Wang C*, Chen X, Takada M, Fan C, Zheng X, Wen H, Liu Y, Wang CG, Pestell RG, Kaelin WG Jr, Liu XS and Zhang Q (2015). EglN2 Associates with NRF-PGC1α Complex and Controls Mitochondrial Function in Breast Cancer. EMBO J (2015) Dec 2; 34(23): 2953-70, (*:equal contribution)
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, Ehrenberger T, Lim E, Liu W, Bronson RT, Bowden M, Brock J, Krop IE, Dillon DA, Gygi SP, Mills GB, Richardson AL, Signoretti S, Yaffe MB and Kaelin WG Jr. Phosphorylation of ETS1 by Src family kinase member prevents its recognition by the COP1 tumor suppressor. Cancer Cell, 2014, Aug 11; 26(2): 222-234.
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).