A Novel Fifth Hexokinase, HKDC1, Mediates NASH-Induced Liver Cancer Through Modulating Mitochondrial Function
Abstract
Objective and Rationale: Obesity is a metabolic disorder and is a global health concern in the modern world. One in three persons in the United States is afflicted with obesity. This results in increased risk of liver disease specifically known as non-alcoholic fatty liver disease (NAFLD). NAFLD is an umbrella term that encompasses a spectrum of liver anomalies ranging from simple fat accumulation (steatosis) to non-alcoholic steatohepatitis (NASH) to the life-threatening condition known as cirrhosis. Cirrhosis can eventually lead to liver cancer, of which hepatocellular carcinoma (HCC) is the most prevalent form. Recent studies also strongly suggest that liver disease present in obese people enhances the risk of liver cancer. However, how obesity together with liver disease increases the risk of liver cancer is still unknown. Hexokinases (HKs) are proteins that help trap glucose in cells where it is further broken down into other metabolites that feed various pathways essential for life. HKs are frequently shown to be targets of proteins that promote cancer (oncogenes), which enhance the expression of HKs. Our team recently discovered a previously unknown HK (hexokinase domain containing 1, HKDC1), and we have data which shows that this novel HK is linked to the progression of both NASH and HCC. We also have data that shows that HKDC1 can interact with the powerhouse of the cell (mitochondria), which plays an important role in NASH and HCC progression. Taking all this data into consideration, we hypothesize that this novel hexokinase HKDC1 plays a role in the progression of both NASH and HCC and it drives the progression of one disease to another (NASH to HCC). We also hypothesize that HKDC1 interaction with the mitochondria is essential for its role in disease progression. Career Goals: The PI for this proposal, Dr. Khan, is an emerging researcher with expertise in the areas of metabolism and cancer metabolism. His recent work on liver cancer has brought forward new insights into how metabolic changes drive the progression of cancer and how they can be best exploited for better intervention and treatment strategies. Furthermore, he has Dr. Layden as a mentor, who is an expert in the area of metabolic syndrome and Dr. Hay as a co-mentor, who is an established cancer researcher and a pioneer in the areas of cancer metabolism and in particular, liver cancer. The career goal for Dr. Khan is to provide break-throughs in cancer treatment, thereby touching the lives of cancer patients. His long-term professional goal is to establish himself as a successful PI and be a pioneer in the area of liver cancer. This grant would provide him the required training, mentorship, and financial support to establish himself as a successful liver cancer researcher. Impact: (a) Deliverables and applicability: Cancer intervention and treatment is a global crisis and has always been a challenge for the scientific and medical community. Furthermore, common disease conditions such as obesity and liver disease, which are prevalent in the world today, increase both the risk and complexity of liver cancer. We have identified a novel protein (HKDC1), and we have evidence showing that it is involved in the progression of both liver disease and liver cancer. Thus, we hypothesize that this novel protein may be the missing link in our current understanding of the complexities of these diseases. The successful completion of this project will bring forward this novel candidate gene as an actionable target that can be exploited for the intervention and treatment of cancer. (b) Direct applicability to military and Veterans: Research shows that NAFLD is a growing concern and the main risk factor for HCC in the US military and Veterans, particularly among patients also diagnosed with other metabolic disorders such as diabetes and obesity. The aftermath of this trend is that readiness for performing service is affected. The successful completion of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010650
Entities
People
- Wasim Khan
Organizations
- United States Army
- University of Illinois at Chicago