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Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells.

ABSTRACT:

Abstract

Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.

SUBMITTER: Watanabe T

PROVIDER: S-EPMC10945144 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells.

Watanabe Tatsuro T Yamamoto Yuta Y Kurahashi Yuki Y Kawasoe Kazunori K Kidoguchi Keisuke K Ureshino Hiroshi H Kamachi Kazuharu K Yoshida-Sakai Nao N Fukuda-Kurahashi Yuki Y Nakamura Hideaki H Okada Seiji S Sueoka Eisaburo E Kimura Shinya S

Blood advances 20240301 6

<h4>Abstract</h4>Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrant ...[more]

PMID: 38190613

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Project description:BackgroundLysine acetylation is a critical post-translational modification regulating tumor initiation and progression. Lysine acetyltransferase 7 (KAT7)-mediated lysine acetylation is frequently dysregulated in cancer. However, the role of KAT7-mediated lysine acetylation in hepatocellular carcinoma (HCC) progression remains unclear.MethodsBioinformatic analysis was used to investigate the expression, clinicopathological characteristics and diagnostic prognostic value of KAT7 in HCC. CCK-8 assays, colony-forming assays, apoptosis assays and nude mouse xenograft models were utilized to detect the oncogenic functions of KAT7 in HCC. Immunoprecipitation (IP) assay and mass spectrometry (MS) analysis were performed to identify the KAT7-binding protein Y-box binding protein 1 (YBX1). Transcriptome sequencing and functional enrichment analysis were employed to elucidate the downstream pathway regulated by KAT7 and YBX1. Chromatin immunoprecipitation (ChIP) assay was used to evaluate YBX1 binding to the promoter regions of ribonucleotide reductase regulatory subunit M2 (RRM2) and thymidine kinase 1 (TK1). Weighted gene co-expression network analysis and selection operator regression analysis were used to build risk prediction models.ResultsThis study demonstrated that elevated KAT7 expression is associated with poor prognosis in HCC patients. Knockdown of endogenous KAT7 in HCC cells attenuated tumorigenic phenotypes associated with cell proliferation, colony formation and orthotopic xenograft tumor growth, indicating a pro-tumorigenic role of KAT7 in HCC. YBX1 was identified as a novel non-histone substrate for KAT7, and the E508 residue of KAT7 is essential for binding. Following the functional enrichment analysis, KAT7 and YBX1 were correlated with nucleotide metabolism. Furthermore, KAT7 binds to YBX1 and modulates its post-translational expression, which enhances the transcriptional activity of the central nucleotide metabolism enzymes RRM2 and TK1. Additionally, we constructed a novel prognostic prediction model based on KAT7, YBX1, RRM2 and TK1, which validated the predictive accuracy and prognostic value of KAT7-mediated acetylation is consistent with clinical outcomes in HCC.ConclusionsOur findings highlight that KAT7 acetylates YBX1 and promotes HCC progression by reprogramming nucleotide metabolism, offering therapeutic implications.

Dataset Information

Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells.

Abstract

Publications

Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells.

Similar Datasets

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