School of Medicine
Area of interest
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 the 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 the potential EglN2 substrates that regulate 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 VHL mutations 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 has 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.
Awards and Honors
2009 Terri Brodeur Breast Cancer Foundation Postdoctoral Fellowship
2010 Ruth L. Kirschstein National Research Service Award (NRSA)
2011 NIH Pathway to Independence (K99/R00) Award
2014 Kimmel Scholar Award, Sidney Kimmel Foundation
2015 V Scholar Award, The V Foundation for Cancer Research