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.

 There are two main lines of research in Zhang Lab: 

  1. We are focusing on studying the oxygen sensing signaling in breast cancer. In this line of research, we focus on characterizing the function of 2-oxoglutarate-depedent dioxygenase enzymes in breast cancer, especially in more malignant triple negative breast cancer (TNBC). We are using integrated approaches, including mass spectrometry, functional screening, metabolomics, xenografts, and mouse models to characterize the function of these enzymes in breast cancer. More importantly, we are developing small molecular inhibitor screening to identify potential inhibitors that can be used to treat breast cancer. Some of our recent publications include Nature Commun (2019, PMID 31729379), Cancer Discov (2020, PMID 32690540). 
  1. Another major line of research in the lab focuses on kidney cancer, especially clear cell renal cell carcinoma (ccRCC) that accounts for 70-80% of all kidney cancer. We are particularly interested in studying VHL regulatory pathways as well as potential synthetic lethality target for ccRCC that display VHL loss. For example, we are utilizing genome-wide unbiased in vitroexpression strategy coupled with GST-binding screening and identified ZHX2 and SFMBT1 to be new pVHL targets in ccRCC (Science, 2018, PMID 30026228; Mol Cell, 2020, PMID 32023483). We identified TBK1 as a potential synthetic lethality target for VHL-loss in kidney cancer (Cancer Discov, 2020, PMID 31810986). In addition, we also worked on regulatory pathways for HIF2a by identifying USP37 as a bona fid deubiquitinase for HIF2a in kidney cancer (PNAS, 2020, PMID 32461361). We are developing improved version of genome-wide in vitro expression library screening at this time to identify other important regulatory pathways in kidney cancer.