Transketolase Deficiency Protects the Liver from DNA Damage by Increasing Levels of Ribose 5-Phosphate and Nucleotides

Li, Minle; Lu, Ying; Li, Yakui; Tong, Lingfeng; Gu, Xiaochuan; Meng, Jian; Zhu, Yemin; Wu, Lifang; Feng, Ming; Tian, Na; Zhang, Ping; Xu, Tian‐Le; Lin, Shuhai; Tong, Xuemei

doi:10.1158/0008-5472.can-18-3776

Cited by 43 publications

(41 citation statements)

References 44 publications

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“…Specifically, TKT can promote the development of HCC in a non-metabolic manner via its nuclear localization and EGFR pathway [33]. Loss of TKT in the liver increased apoptosis, reduced cell proliferation, decreased TNF-α, IL-6, and STAT3 levels, and alleviated DEN/HFD-induced hepatic steatosis and fibrosis, highlighting a key role for TKT in promoting genome instability during liver injury and tumor initiation [34]. CBFA2T2 (also known as MTGR1), a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors, can significantly predict the survival of renal cell carcinoma (RCC) patients.…”

Section: Discussionmentioning

confidence: 99%

A novel seven-gene signature as Prognostic Biomarker in Hepatocellular Carcinoma

et al. 2020

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Purpose: Our study is designed to develop and certify a promising prognostic signature for hepatocellular carcinoma (HCC). Materials and methods: We retrospectively analyzed mRNA expression profiles and clinicopathological data fetched from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We formulated a prognostic seven-gene signature composed of differentially expressed mRNAs (DEmRNAs) between HCC and nonneoplastic tissues through univariate Cox regression analysis. The receiver operating characteristic (ROC) curve, survival analysis and multivariate Cox regression analysis as well as nomograms were utilized to assess the prognostic performance of the seven-gene signature. Results: The risk score based on a seven-gene signature categorized HCC subjects into a high-and low-risk group. There was significantly discrepant overall survival (OS) between patients in both groups and the corresponding ROC curve revealed a satisfactory predictive performance in HCC survival in both TCGA and GSE76427 cohort. Multivariate Cox regression analysis demonstrated that a seven-gene signature was an independently prognostic factor for HCC. Nomograms combining this prognostic signature with significant clinical characteristics conferred a crucial reference to predict the 1-,3-and 5 years OS. Conclusions: Our study defined a promising seven-gene signature and nomogram model to forecast the OS of HCC patients, which is instrumental in clinical decision and personalized therapy.

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Section: Discussionmentioning

confidence: 99%

A novel seven-gene signature as Prognostic Biomarker in Hepatocellular Carcinoma

et al. 2020

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“…Li et al . [51] reported that transketolase (TKT), which is a part of a branch of the PPP that is known to sustain HCC progression, modulates ribose 5‐phosphate (R5P) expression and nucleotide synthesis (Table 1 and Figure 2E). Du et al .…”

Section: Glucose Metabolismmentioning

confidence: 99%

“…Though PPP is related to the Warburg effect, its precise role in cancer metabolism remains unclear. Li et al [51] reported that transketolase (TKT), which is a part of a branch of the PPP that is known to sustain HCC progression, modulates ribose 5-phosphate (R5P) expression and nucleotide synthesis ( Table 1 and Figure 2E). Du et al [52] found that the p53 family member TAp73 activates the expression of the G6PD and triggers the biosynthesis of NADPH and ribose with attenuated ROS in osteosarcoma (Table 1 and Figure 3).…”

Section: Pppmentioning

confidence: 99%

New insights into molecules and pathways of cancer metabolism and therapeutic implications

Tang

Zhu

et al. 2020

Cancer Communications

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Cancer cells are abnormal cells that can reproduce and regenerate rapidly. They are characterized by unlimited proliferation, transformation and migration, and can destroy normal cells. To meet the needs for cell proliferation and migration, tumor cells acquire molecular materials and energy through unusual metabolic pathways as their metabolism is more vigorous than that of normal cells. Multiple carcinogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells, including glucose, lipid, and amino acid metabolism. The distinct metabolic signatures of cancer cells reflect that metabolic changes are indispensable for the genesis and development of tumor cells. In this review, we report the unique metabolic alterations in tumor cells which occur through various signaling axes, and present various modalities available for cancer diagnosis and clinical therapy. We further provide suggestions for the development of anti‐tumor therapeutic drugs.

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“…Recent research demonstrated that an altered metabolism may affect genome stability by palying a role in DNA damage 17 . As it is known, integrity of the DNA structure is the basis for the viability of all living cells and organisms, given that it is the main carrier of genetic information.…”

Section: Introductionmentioning

confidence: 99%

Silencing Sirtuin5 induces DNA damage by suppressing the pentose phosphate pathway in a demalonylation-dependent manner: A possible target for anticancer therapy in CRC

Wang

Chen²,

Wang³

et al. 2021

Preprint

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A previous study by our research group showed that sirtuin5 (SIRT5), a member of the class III NAD＋-dependent deacetylase family, is highly expressed in colorectal cancer (CRC). The present study showed that deletion of SIRT5 induced cell cycle arrest and apoptosis as a result of continuous and irreparable DNA damage in CRC cells, a consequence of the impaired production of ribose-5-phosphate (R5P) which is essential for nucleotide synthesis. Consistently, the cell cycle arrest and apoptosis induced by SIRT5 silencing could be reversed by supplementation with four nucleotides. Moreover, metabolic profiling revealed that silencing of SIRT5 could inhibit the non-oxidative pentose phosphate pathway (PPP), which produces R5P, required for base ribosylation. Notably, SIRT5 activates transketolase (TKT), the key enzyme in the cellular non-oxidative PPP, by mediating its lysine demalonylation through the interaction between SIRT5 and TKT. Furthermore, the results demonstrated that TKT is essential for the SIRT5-induced malignant phenotypes of CRC, both in vivo and in vitro. These results therefore revealed that the increased lysine malonylation levels of TKT caused by silencing SIRT5 suppresses non-oxidative pentose phosphate metabolism, leading to a low-nucleotide pool. This in turn induces DNA damage in tumor cells and inhibits proliferation, suggesting that SIRT5 may serve as a potential anticancer target.

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Transketolase Deficiency Protects the Liver from DNA Damage by Increasing Levels of Ribose 5-Phosphate and Nucleotides

Cited by 43 publications

References 44 publications

A novel seven-gene signature as Prognostic Biomarker in Hepatocellular Carcinoma

A novel seven-gene signature as Prognostic Biomarker in Hepatocellular Carcinoma

New insights into molecules and pathways of cancer metabolism and therapeutic implications

Silencing Sirtuin5 induces DNA damage by suppressing the pentose phosphate pathway in a demalonylation-dependent manner: A possible target for anticancer therapy in CRC

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