PROJECT SUMMARY – Role of JMJD4 in Pancreatic Cancer In 2023, nearly 50,000 patients will die from pancreatic cancer in the US. This malignancy has one of the worst survival rates, indicating the urgent need for better therapies. A more comprehensive understanding of driving forces in pancreatic cancer may furnish novel ideas how to curtail this disease. JMJD4 is an enzyme that has been implicated in protein lysine hydroxylation and demethylation. However, the precise physiological functions of JMJD4 and its mechanisms of action have remained unresolved. Our preliminary data demonstrate that JMJD4 is upregulated in pancreatic tumors and JMJD4 ablation reduces growth and clonogenicity of human pancreatic cancer cells, while JMJD4 overexpression may stimulate cell invasion. Further, we provide evidence that JMJD4 interacts with two transcription factors involved in the development of tumors and chemoresistance: the stress response mediator NRF2 and HIF-2a, a major component of the hypoxia response pathway. This suggests various potential mechanisms by which JMJD4 could affect pancreatic cancer cells. Based on these and other preliminary data, we posit that JMJD4 promotes pancreatic tumorigenesis. Moreover, we hypothesize that JMJD4 functions, at least in part, through modulating NRF2 and HIF-2a. To test these hypotheses, we propose two specific aims: (i) To determine the role of JMJD4 in pancreatic cancer cells. (ii) To reveal how JMJD4 acts at the molecular level. Completion of these studies will greatly advance our mechanistic understanding of JMJD4 and its role in pancreatic tumors. Furthermore, our research may nominate the JMJD4 enzyme as a novel target for the treatment of pancreatic cancer. Because JMJD4 is not essential in normal cells, small molecule inhibitors of JMJD4 are predicted to have minimal side effects, a highly desirable feature. Lastly, insights gained here likely have implications for the treatment of other diseases, including colorectal and lung cancer, where JMJD4 is also overexpressed.