SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

Xu, Shuangnian; Wang, Tian-Shi; Xi, Li; Wang, Yiping

doi:10.1038/srep32734

Cited by 92 publications

(102 citation statements)

References 52 publications

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“…Thus SIRT2 may provide an additional link between K-Ras4a signaling and cellular metabolism. Given that Ras proteins play critical roles in many human cancers, SIRT2, as a Ras regulator, may be an important therapeutic target for cancer, which is consistent with several recent reports 50,53, 54,57,58,85–87 . The physiological and pathophysiological roles of SIRT2 thus merit further investigation.…”

Section: Discussionsupporting

confidence: 89%

“…One caveat of the result, however, was that Sirt2 KD still decreased the colony formation induced by K-Ras4a-G12V-3KR or H-Ras-G12V, whose lysine fatty acylation was not regulated by SIRT2. This is not unexpected because SIRT2 is known to exert tumor-promoting functions by deacetylating various targets 50–58 . Thus, the effect of Sirt2 KD on K-Ras4a-G12V-3KR- and H-Ras-induced transformation might be attributed to other substrates for SIRT2.…”

Section: Resultsmentioning

confidence: 95%

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SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

Jing

Zhang

et al. 2017

Preprint

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12Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many 13 human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling 14 pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras 15 splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-16 translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide 17 (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further 18 demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-19 Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study 20 identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of 21GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological 22 significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation. 23 24 25. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 95%

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

Jing

Zhang

et al. 2017

Preprint

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“…The up-regulation of G6PD activity in SIRT6 overexpressing cells may be related to a direct G6PD protein modification by SIRT6 through one of its enzymes: deacetylase, deacylase, or ADP-ribosyltransferase. Alternatively, the increased G6PD activity may be caused by augmented SIRT2 activity in cells with increased NAD + levels, because SIRT2 has been reported to activate G6PD in acute myeloid leukemia cells (50). SIRT2 inhibition suppressed G6PD activity, reducing proliferation of leukemia cells, indicating that SIRT2 may represent a promising target for therapeutic applications in leukemia.…”

Section: Discussionmentioning

confidence: 99%

SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells

et al. 2018

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Nicotinamide phosphoribosyltransferase (NAMPT) is the rate‐limiting enzyme in the NAD+ salvage pathway from nicotinamide. By controlling the biosynthesis of NAD+, NAMPT regulates the activity of NAD+‐converting enzymes, such as CD38, poly‐ADP‐ribose polymerases, and sirtuins (SIRTs). SIRT6 is involved in the regulation of a wide number of metabolic processes. In this study, we investigated the ability of SIRT6 to regulate intracellular NAMPT activity and NAD(P)(H) levels. BxPC‐3 cells and MCF‐7 cells were engineered to overexpress a catalytically active or a catalytically inactive SIRT6 form or were engineered to silence endogenous SIRT6 expression. In SIRT6‐overexpressing cells, NAD(H) levels were up‐regulated, as a consequence of NAMPT activation. By immunopurification and incubation with recombinant SIRT6, NAMPT was found to be a direct substrate of SIRT6 deacetylation, with a mechanism that upregulates NAMPT enzymatic activity. Extracellular NAMPT release was enhanced in SIRT6‐silenced cells. Also glucose‐6‐phosphate dehydrogenase activity and NADPH levels were increased in SIRT6‐overexpressing cells. Accordingly, increased SIRT6 levels reduced cancer cell susceptibility to H2O2‐induced oxidative stress and to doxorubicin. Our data demonstrate that SIRT6 affects intracellular NAMPT activity, boosts NAD(P)(H) levels, and protects against oxidative stress. The use of SIRT6 inhibitors, together with agents inducing oxidative stress, may represent a promising treatment strategy in cancer.—Sociali, G., Grozio, A., Caffa, I., Schuster, S., Becherini, P., Damonte, P., Sturla, L., Fresia, C., Passalacqua, M., Mazzola, F., Raffaelli, N., Garten, A., Kiess, W., Cea, M., Nencioni, A., Bruzzone, S. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB J. 33, 3704–3717 (2019). http://www.fasebj.org

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“…4B). Second, HCT116 and SW480 cells were treated with the SIRT2-specific inhibitor AGK2, and endogenous E-cadherin acetylation was measured (41). Inhibition of SIRT2 by AGK2 markedly enhanced E-cadherin acetylation.…”

Section: Sirt2 Was the Deacetylase For E-cadherinmentioning

confidence: 99%

Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing β-Catenin Activity

Zhao

Zhang

et al. 2019

Molecular Cancer Research

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The E-cadherin/b-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, Ecadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1. In the nucleus, E-cadherin was acetylated by CREB-binding protein at Lysine 870 and Lysine 871 in its b-catenin-binding domain, and the acetylation can be reversed by SIRT2. Acetylation of nuclear E-cadherin attenuated its interaction with b-catenin, which therefore released b-catenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration. Further study showed that acetylation level of nuclear E-cadherin had high prognostic significance in clinical colorectal samples. Taken together, our findings reveal a novel mechanism of tumor progression through posttranslational modification of E-cadherin, which may serve as a potential drug target of tumor therapy.Implications: This finding that acetylation of nuclear E-cadherin regulates b-catenin activity expands our understanding of the acetylation of E-cadherin promotes colorectal cancer cell growth and suggests novel therapeutic approaches of targeting acetylation in tumors.

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SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

Cited by 92 publications

References 52 publications

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells

Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing β-Catenin Activity

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