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Description
Hepatocellular carcinoma (HCC) accounts for >80% of patients with liver cancer and is one of
the leading causes of cancer-associated mortalities, both worldwide and in the United States.
Recent evidence highlights the involvement of YRDC (YrdC-threonylcarbamoyltransferase
domain-containing protein), a tRNA modifying enzyme, in tumor growth via N6-
threonylcarbamoylation (t6A) of tRNA in various cancer types, including HCC. Additionally,
YRDC has been shown to be overexpressed in different types of cancer and associated with
chemotherapeutic drug resistance as well as poor prognosis in HCC patients. However, the
precise molecular mechanisms underlying YRDC overexpression in cancers and its involvement
in the regulation of tumor metabolism remain unknown. The objective of our study is to define
the mechanisms by which YRDC drives cellular growth and investigate the potential of targeting
YRDC in cancers, with a specific focus on HCC. Our preliminary data, employing metabolomic
and isotope tracing approaches, have shown that YRDC can act as a novel regulator of one-
carbon metabolism and purine synthesis in several cancer cells, including HCC cells. We
demonstrate that YRDC depletion reduces flux through one-carbon metabolism, thereby
restricting the availability of substrates for the synthesis of de novo purine nucleotides. In light of
these findings, this proposal focuses on studying YRDC and its impact on tumor metabolism
using HCC as a model. We hypothesize that YRDC promotes tumor growth by activating one-
carbon metabolism, thereby stimulating de novo purine synthesis. Consequently, targeting
YRDC represents a potentially effective strategy against HCC. We will define the mechanisms
underlying YRDC upregulation in HCC, we will use isogenic cell settings deleted for the tumor
suppressor P53 and expressing mutant KRAS, and examine the role of the MAPK/ERK
downstream of KRAS in the regulation of YRDC mRNA and protein levels (Aim1). Then, we will
determine the molecular mechanisms by which YRDC stimulates one-carbon metabolism and
purine synthesis in HCC cells (Aim2). Finally, we willexamine the therapeutic potential of
suppressing YRDC to improve HCC, and/or sensitize HCC to chemotherapy (Aim3). Overall, the
proposal is significant because it will identify novel regulators of one carbonmetabolism and the
de novo purine synthesis pathways, clarify the tumor pro-growth function of
YRDC, and identify a novel drug target in HCC treatment. The project is highly innovative
because, to date,YRDC has not been linked to the regulation of one-carbon metabolic pathway.
The proposal will provide a stepping-stone to aid the applicant to establish an independent
research career and the work performed under this award will be used to generate NIH R01
grant proposals.
Status | Active |
---|---|
Effective start/end date | 3/1/17 → 12/31/26 |
Funding
- National Institute of General Medical Sciences
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Projects
- 1 Active
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University of Kentucky Center for Cancer Metabolism (Admin Core)
Zhou, B. (PI), Brainson, C. (CoI), Chaiswing, L. (CoI), D'Orazio, J. (CoI), Duncan, E. (CoI), Fan, W.-M. (CoI), Fong, K. W. (CoI), Hao, Z. (CoI), Hersh, L. (CoI), Higashi, R. (CoI), Jia, J. (CoI), Lane, A. (CoI), Liu, J. (CoI), Liu, X. (CoI), Moseley, H. (CoI), Myint, Z. (CoI), Rellinger, E. (CoI), Thorson, J. (CoI), Van Eldik, L. (CoI), Vanderford, N. (CoI), Wang, C. (CoI), Weiss, H. (CoI) & Yalniz, F. (CoI)
National Institute of General Medical Sciences
3/1/17 → 12/31/26
Project: Research project