SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis

Ma, Yuzhen; Qi, Yijun; Wang, Lei; Zheng, Zhaoxu; Zhang, Yue; Zheng, Junfang

doi:10.1016/j.freeradbiomed.2019.01.030

Cited by 76 publications

(48 citation statements)

References 30 publications

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“…Another important function of Gln metabolism is to provide precursors for glutathione production, which helps to maintain the oxidative status of cells. Indeed, GLS is directly linked to redox balance in cancer cells [25]. Therefore, Gln and its metabolites can provide raw materials for cell growth and enhance cell proliferation and growth.…”

Section: Discussionmentioning

confidence: 99%

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism

et al. 2019

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Background Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. Methods Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. Results Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC’s growth and autophagy in vitro and / or in vivo. Conclusions CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

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Section: Discussionmentioning

confidence: 99%

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism

et al. 2019

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“…383 SIRT5-catalyzed demalonylation and inactivation of SDHA block the TCA cycle and induce succinate accumulation, promoting tumorigenesis and drug resistance. 383,384 Additionally, sirtuins also regulate the expression of metabolic enzymes via transcription factors, such as HIF-1α. SIRT3 enhances the enzymatic activities of SOD2 and IDH2 to limit ROS levels, which repress the metabolism reprogramming in cancer cell via destabilizing HIF-1α, thereby repressing tumor growth.…”

Section: Abnormal Nad + Metabolism In the Pathophysiological Conditionmentioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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“…However, SIRT3 was reported to be up-regulated in the mitochondrial fraction of human RCC tissues, and knockdown of SIRT3 inhibited RCC cell proliferation and tumor growth in vivo (14). SIRT5 promotes KIRC tumorigenesis through inhibiting SDHA succinylation and silencing SIRT5 inhibited RCC cell proliferation (15).…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

Tan

Peng

et al. 2020

Front. Oncol.

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Sirtuins, class III histone deacetylases, are involved in multiple biological processes in cancer initiation and progression. However, the diverse expression patterns and prognostic values of sirtuins in cancers have yet to be elucidated. In this study, we first evaluated the expression and prognostic values of sirtuins in multiple cancer cohorts using publicly available TCGA pan-cancer datasets. Pan-cancer survival analysis indicated that 6 out of 7 sirtuin family members were significant associated with prognosis of clear cell renal cell carcinoma (KIRC) patients. SIRT1, SIRT3, SIRT4, and SIRT5 were associated with favorable prognosis of KIRC patients, while SIRT6 and SIRT7 were associated with unfavorable prognosis. The expression levels of SIRT4 and SIRT5 in KIRC tissues were lower than that in normal tissues, while SIRT6 and SIRT7 were higher in KIRC tissues. The expression levels of SIRT1, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly correlated with tumor stage and histological grade. DNA methylation may contribute to the dysregulation of sirtuins. Finally, GSEA was conducted to predict the potential functions of sirtuins in KIRC. Our results may provide novel insights for the development of sirtuins-based cancer therapy in KIRC.

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SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis

Cited by 76 publications

References 30 publications

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

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