Cancer metabolism
My lab studies how nitrogen metabolism affects liver cancer development. This project is supported by 2 NIH R01 grants: one is to focus on the role of glutamine synthetase, and the other is to focus on the urea cycle enzymes. These two ammonia detoxification pathways play important roles in normal liver function. Defective ammonia clearance leads to pathological disorders such as encephalopathy. Recent literature and our own findings indicate that both glutamine synthesis and urea cycle pathways are involved in liver cancer development. Clinical data also indicate a strong correlation between defective ammonia clearance and liver cancer. We are studying the hypothesis that defective ammonia clearance is a risk factor and plays a major role in liver cancer development. To do this, we will modulate the expression of several ammonia-clearance enzymes and test the effect in mouse liver cancer models. We will also study how oncogenes such as beta-catenin regulate the expression of these enzymes including glutamine synthetase and urea cycle enzymes.
Novel tumor suppressors in B-cell lymphoma
We are studying the roles of several novel potential tumor suppressor genes in B-cell lymphoma. Via a CRISPR/Cas9 screening in an interleukin 3 (IL3)-dependent pro-B cell line Ba/F3, we have identified a number of hits whose loss of function leads to IL3 independence. We are currently focusing on three genes that are localized to human chromosome 6q, namely OSTM1, ZBTB24, and SLC35A1. These genes have different molecular functions: OSTM1 is a putative ubiquitin E3 ligase, ZBTB24 is a transcriptional factor, and SLC35A1 is a sialic acid transporter that facilitates protein sialylation. Our preliminary data indicate that knocking out these genes leads to increased cell growth and transformation in Ba/F3 cells, and combined genetic ablation with a known tumor suppressor CDKN2A in B-cell lineage leads to enhanced B-cell lymphoma in all three gene knockout mouse models. We will continue characterizing these mouse models, and study the molecular mechanisms how the three genes may function to regulate cell growth, survival, and transformation. Ultimately, we aim to uncover the molecular mechanisms as to how the novel tumor suppressors function, and ultimately to discover therapeutic strategies for treating the malignancy of the lymphoid organs.