Research Interests
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听痴贬尝听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听in vitro听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听VHL听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听VHLmutations also play major roles in sporadic renal cell cancer. Loss of听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听in vitro听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.
Selected Publications
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听Zhang Q听(2018). VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.听Science, July 20; 361 (6399): 290-295. (*: equal contribution).
Zhang Q听(2018).听 Correcting COMPASS Dysfunction in Cancer.听Science Translational Medicine听Vol.10, Issue 444, eaau0466.
Zhang Q听(2018).听 RNase Moonlights as a Cancer Instigator.听Science Translational Medicine听Vol. 10, Issue 436, eaat3892.
Zhang J and听Zhang Q听(2018).听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,听Zhang Q, Gromeier M.听听Mol Cell Biol.听2018 Mar 12. pii: MCB.00647-17. doi: 10.1128/MCB.00647-17. PubMed PMID: 29530922.
Zhang Q听(2018) Stressing Myc Driven Cancer Out.听Science Translational Medicine听Vol. 10, Issue 428, eaar7535.
Wang L, Wrobel JA, Xie L, Li D, Zurlo G, Shen H, Yang P, Wang Z, Gunawardena HP,听Zhang Q听and Chen X (2018). Novel RNA-affinity proteogenomics dissects the interpatient tumor-phenotypic heterogeneity for revealing personalized markers for precision prognosis.听Cell Chem Biol听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听Zhang Q听(2017). Exploring the Role of CENP-A Ser18 Phosphorylation in CIN and tumorigenesis.听Cell Cycle听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听Zhang Q# (2017). FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/Cdk2-mediated phosphorylation of CENP-A.听Cancer Research听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,听Zhang Q, Parker JS, Yeh JJ, Moffitt RA, Leung JY and Kim WY (2017).听Myc听activation cooperates with听Vhl听and听Ink4a/Arf听loss to induce clear renal cell carcinoma.听Nature Communication听2017 Jun 8;8:15770. doi: 10.1038/ncomms15770. PubMed PMID: 28593993.
Di Conza G, Cafarello ST, Zheng X,听Zhang Q听and Mazzone M (2017). PHD2 Targeting Overcomes Breast Cancer Cell Death Upon Glucose Starvation in a PP2A/B55a-Mediated Manner.听Cell Reports, March 21st, Vol 18, 2836-2844. PMC5378984
Takada M*, Zhuang M*, Inuzuka H, Zhang J, Zurlo G, Zhang J and听Zhang Q听(2017). EglN2 Contributes to Triple Negative Breast Tumorigenesis By Functioning as a Substrate for the FBW7 Tumor Suppressor.听Oncotarget听2017 Jan 24;8(4):6787-6795. doi: 10.18632/oncotarget.14290. (*: equal contribution) PMC5351669
Zurlo G, Guo J, Takada M, Wei W,听Zhang Q. New Insights into Protein Hydroxylation and Its Important Role in Human Diseases.听BBA-Reviews on Cancer,听2016听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,听Zhang Q, Asara JM, Kaelin WG JR, Wei W. pVHL suppresses kinase activity of Akt in a proline-hydroxylation dependent manner.听Science,听2016 August 26; 353 (6302):929-932.
Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA, Patel H,听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.听Cell听2016, Jun 30: 166 (1): 126-139.
Zhang J, Zheng X and听Zhang Q听(2015). EglN2 Positively Regulates Mitochondrial Function in Breast Cancer.听Mol Cell Oncol.听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听Zhang Q听(2015). EglN2 Associates with NRF-PGC1伪 Complex and Controls Mitochondrial Function in Breast Cancer.听EMBO J听(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听Zhang Q*. Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.听Genes & Development, 2014 Jul 1;28(13):1429-44 (*:co-correspondent)
Lu G,听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.听Cancer Cell, 2014, Aug 11; 26(2): 222-234.
Chen X, Iliopoulos D*,听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 HIF1伪 pathway.听Nature, 2014 Apr 3;508 (7494):103-7. (*: equal contribution)
Zhang Q, Yang H. The roles of VHL-dependent ubiquitination in signaling and cancer.听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,听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.听Proceedings of the National Academy of Sciences, 2011; 108(33): 13379-86.
Li Y,听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.听Cancer Research, 2011; 71(24): 7481-9.
Inuzuka H, Tseng A, Gao D, Zhai B,听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.听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.听Cancer Cell, Nov 3;16(5):413-24. (*: co-first author)
Nozawa H, Howell G, Suzuki S,听Zhang Q, Qi Y, Klein-seetharaman J, Wells A, Grandis JR, Thomas SM (2008). Combined inhibition of PLC纬-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion.听Clinical Cancer Research, Jul 1; 14 (13): 4336-4344.
Wang J, Singh N,听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).听Journal of the National Cancer Institute, April 2; 100(7): 502-512.
Young AP, Schlisio S, Minamishima YA,听Zhang Q, Li L, Grisanzio C, Signoretti S, Kaelin WG (2008). pVHL Loss Actuates a HIF-independent Senescence Program Mediated by pRb and p400.听Nature Cell Biology, Mar 1; 10(3): 361-369.
Seethala RR, Gooding WE, Handler PN, Collins B,听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.听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.听Molecular Cancer Therapeutics, Apr;6(4):1414-24.
Thomas SM, Bhola N,听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.听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-伪 converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.听Proceedings of the National Academy of Sciences, May 2: 103 (18): 6901-6906.
Xi S, Mark K, Dyer K,听Zhang Q, Challet R, Ferris RA, Hunt J, Grandis JR (2006). Downregulation of STAT1 by promoter methylation is critical for squamous cell carcinogenesis.听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.听Cancer Research, Sep 1; 64(17):6166-73.
Xi S,听Zhang Q, Gooding WE, Smithgall TE, Grandis JR (2003). Constitutive activation of Stat5b contributes to carcinogenesis in Vivo.听Cancer Research, 63 (20): 6763-6771.
Xi S,听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.听J. Biol.Chem.听Vol 278 p31574-31583.
Lui VWY*, Thomas SM*,听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.听Oncogene, 22(40): 6183-6193 (*: co-first author).
