Grants and Contracts per year
Grants and Contracts Details
Project summary Histone-modifying enzymes play a central role in controlling gene expression, dysregulating expression of these enzymes contribute significantly to the initiation, progression, metastasis as well as metabolism. One of these enzymes, LSD1, is critical for these progresses. However, the mechanisms by which LSD1 stability is regulated are poorly defined. Our preliminary results reveal a novel mechanism for LSD1 stabilization. We identified that RNF20 is a specific E3 ligase for LSD1 stabilization. Furthermore, we demonstrate that LSD1 is a target of CDK9 and that the phosphorylation induced by CDK9 is important for RNF20-mediated LSD1 stabilization. Metabolic shift from mitochondrial to glycolytic metabolism is the hallmark of most cancer cells. Based on our preliminary data, we hypothesize that the CDK9-dependent phosphorylation is critical for RNF20-mediated LSD1 stabilization, which contributes to increase of glycolytic and suppression of mitochondrial oxidative phosphorylation. The goal of this study is to test this hypothetical model and to determine whether CDK9-RNF20-LSD1 axis is critical for epigenetic plasticity of cancer cell metabolism. We will test our central hypothesis by pursuing two specific aims: 1) To delineate the molecular mechanisms by which CDK9 and RNF20 controls LSD1 stabilization; 2) To define the function and clinical relevance of CDK9-RNF20-LSD1 cascade in cancer metabolism. Completion of these aims will reveal novel molecular mechanisms that control LSD1 stabilization and generate an awareness of RNF20 epigenetically regulating cancer metabolism in cancer. Moreover, our proposed studies will provide the molecular basis for designing novel strategies to combine the LSD1 inhibitors with CDK9 inhibitors to synthetically inhibit tumor growth. We will submit a competitive RO1 grant with the data collected from this project.
|Effective start/end date||1/1/23 → 12/31/23|
- National Institute of General Medical Sciences
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- 1 Active
University of Kentucky Center for Cancer Metabolism (Admin Core)
Zhou, B., Arnold, S., Brainson, C., Cassis, L., D'Orazio, J., Evers, B. M., Fan, W., Fong, K. W., Hersh, L., Higashi, R., Jia, J., Lane, A., Liu, J., Liu, X., Liu, X., Marcinkowski, E., Moseley, H., Rellinger, E., Stromberg, A., Thorson, J., Van Eldik, L., Vanderford, N., Wang, C., Weiss, H., Wu, Y., Xu, R., Zhu, C., St Clair, D., Gentry, M., Hildebrandt, G. & Wang, P.
National Institute of General Medical Sciences
3/1/17 → 12/31/26
Project: Research project