Role of JMJD4 in Breast Cancer - PROJECT SUMMARY – ROLE OF JMJD4 IN BREAST CANCER In 2023, nearly 43,000 women will die from breast cancer in the US, indicating the urgent need for better therapies. A more comprehensive understanding of driving forces in breast 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 breast tumors and JMJD4 ablation can reduce growth and invasion of human breast cancer cells. Further, we provide evidence that JMJD4 interacts with two transcription factors involved in the development of breast cancer 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 may affect breast cancer cells. Based on these and other preliminary data, we posit that JMJD4 promotes breast 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 breast cancer cells. (ii) To reveal how JMJD4 acts through NRF2 and HIF-2a. Completion of these studies will greatly advance our mechanistic understanding of JMJD4 and its role in breast tumors. Furthermore, our research may nominate JMJD4 as a novel target for the treatment of breast cancer. Because JMJD4 is not essential for normal cells, small molecule inhibitors of JMJD4 enzymatic activity 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 colon and lung cancer, where JMJD4 is also overexpressed.
