Elucidating the Role of Protein Dynamics in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) accounts for a majority of liver cancers, and Texas has the highest incidence rate of HCC in the US. Most HCC patients are diagnosed at advanced stages with a low survival rate. The poor clinical outcome is due to a high rate of resistance to conventional chemotherapy and first-line therapy drugs. It is, therefore, critical to understand the basic mechanism of HCC and develop new drug targets to improve treatment. As the liver is the main metabolic organ, liver cells are more prone to oxidative stress. In HCC cells, excess oxidative stress is associated with a disrupted response to reduce DNA damage. The overall goal of this proposal is to study molecular mechanisms for two critical protein systems in response to DNA damage in HCC. The first aim is to study how the human cancer suppressor p53 binds the gene of a specific protein (p21). In my postdoctoral work, I have shown that dynamic interactions between two parts of p53 are key to regulating the p21-gene binding, but the molecular level mechanism is still lacking. By a combination of quantitative experimental techniques, we will study how dynamic protein motions affect p53 activities at the molecular level. p53 is frequently mutated in HCC, and the most prevalent oncogenic mutation is R249S. We will also study how the R249S mutation disrupts the dynamic protein movements of p53. The second aim is to study how a novel protein target in HCC called LanCL1 promotes tumor growth by interacting with another protein named FAM49B. The LanCL1-FAM49B protein interaction is key for HCC tumor growth, but the interfacial structure is unknown. We aim to probe this key protein interface. The potential impact of the proposed research is to provide unprecedented insights into the mechanism of HCC cancer biology. The identified protein interface in the second aim will also provide key insights to guide the development of small molecules with potential to improve the current treatment of HCC.