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Description
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.
Status | Active |
---|---|
Effective start/end date | 1/1/23 → 12/31/23 |
Funding
- National Institute of General Medical Sciences
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Projects
- 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