Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers

Sun, Ramon C.; Dukhande, Vikas V.; Zhou, Zhengqiu; Young, Lyndsay E.A.; Emanuelle, Shane; Brainson, Christine F.; Gentry, Matthew S.

doi:10.1016/j.cmet.2019.08.014

Cited by 88 publications

(90 citation statements)

References 105 publications

(120 reference statements)

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“…Depletion of malin impairs nuclear glycogenolysis by blocking nuclear translocation of PYG. The resulting accumulation of nuclear glycogen is reversed by re-introduction of malin in lung cancer cells which restores nuclear catabolism of glycogen, increases histone acetylation, and decreases growth of non-small-cell lung cancer xenografts in mice (51). This highlights the importance of glycogen beyond a cytoplasmic glucose reservoir, revealing this macromolecule as a key driver of compartmentalized tumor metabolism.…”

Section: Glycogen Driving Carcinogenesismentioning

confidence: 97%

“…Interestingly, PYG via a mechanism involving the E3 ubiquitin ligase malin, can also translocate to the nucleus to drive nuclear glycogenolysis non-small cell in lung cancer, fueling compartmentalized pyruvate production and histone acetylation (51). Aberrant histone acetylation resulting in an altered epigenetic landscape is a hallmark of multiple cancers FIGURE 2 | (A) Impacts of glycogen on cells of the tumor microenvironment.…”

Section: Glycogen Driving Carcinogenesismentioning

confidence: 99%

“…The size and abundance of glycogen facilitate its visualization and use to delineate glycogen-dependent tumors. Hematoxylin and eosin, and periodic acid-Schiff stains are used in routine histopathology assessments to delineate clear cell tumors (9) and antibodies are available to immunohistochemically distinguish glycogen from lipids and glycoproteins (51,88). Glycogen granules can also be readily detected by electron microscopy, and this technique has been used in studies to detect carcinogenesisassociated changes in glycogen content (10,12,32,60,74).…”

Section: Visualizing and Quantifying Tumor Glycogenmentioning

confidence: 99%

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Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

et al. 2020

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Once thought to be exclusively a storage hub for glucose, glycogen is now known to be essential in a range of physiological processes and pathological conditions. Glycogen lies at the nexus of diverse processes that promote malignancy, including proliferation, migration, invasion, and chemoresistance of cancer cells. It is also implicated in processes associated with the tumor microenvironment such as immune cell effector function and crosstalk with cancer-associated fibroblasts to promote metastasis. The enzymes of glycogen metabolism are dysregulated in a wide variety of malignancies, including cancers of the kidney, ovary, lung, bladder, liver, blood, and breast. Understanding and targeting glycogen metabolism in cancer presents a promising but under-explored therapeutic avenue. In this review, we summarize the current literature on the role of glycogen in cancer progression and discuss its potential as a therapeutic target for cancer treatment.

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Section: Glycogen Driving Carcinogenesismentioning

confidence: 97%

Section: Glycogen Driving Carcinogenesismentioning

confidence: 99%

Section: Visualizing and Quantifying Tumor Glycogenmentioning

confidence: 99%

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Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

et al. 2020

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“…Nuclear accumulation of glycogen was recently associated to epigenetic changes in gene expression and cancer (Sun et al, 2019). Moreover, liver cancer is an emerging feature of UCD (Koo et al, 2017;Wang et al, 2019;Wilson et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders

Soria¹,

Perocheau

Sabbata

et al. 2020

Preprint

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Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unraveled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell penetrating autophagy inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and hyperammonemia, and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.

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“…Lysine acetylation is a common posttranslational modification (PTM) regulating protein stability, subcellular localization, and function [17]. Acetylation of histone and nonhistone was reported to be involved in many diseases, including aging-associated chronic inflammation and insulin resistance [18], cancer [19][20][21], colitis [22], and Alzheimer's disease [23]. In previous work, we analyzed the lysine acetylproteome in three primary cervical cancer tissues and corresponding adjacent normal tissues by using the label-free proteomics approach and found that acetylation levels of CLIC1 at lysine 131 were significantly increased in tumor tissues.…”

Section: Introductionmentioning

confidence: 99%

Acetylation stabilizes chloride intracellular channel 1 that exerts a tumor-promoting role by activation of nuclear factor kappa B in cervical cancer

Wang¹,

Li²,

Xu³

et al. 2020

Preprint

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Background: Cervical cancer remains a major cause of cancer-related death in women, especially in developing countries. Previously, we identified that acetylation levels of chloride intracellular channel 1 (CLIC1) at lysine 131 were increased in cervical cancer tissues by using the label-free proteomics approach. The aim of this study was further to determine the role of CLIC1 expression and its acetylation in cervical cancer. Methods: CLIC1 expression and its implications on prognosis in cervical cancer were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) database (gepia.cancer-pku.cn). The effect of CLIC1 on cells was evaluated by Cell Counting Kit (CCK)-8, flow cytometry, wound healing assay, transwell assay, western blotting, and co-immunoprecipitation (Co-IP). In vivo tumor growth was assessed in mouse xenograft models. Results: We found that CLIC1 expression was increased in cervical cancer tissues and cells. The knockdown of CLIC1 significantly reduced cell proliferation, migration, invasion, and in vivo tumorigenesis of cervical cancer cells. Molecularly, nuclear factor kappa B (NF-κB) activity was positively regulated by CLIC1. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB activation, attenuated the tumor-promoting effect of CLIC1. Moreover, CLIC1 acetylation at K131 was upregulated in cervical cancer, which stabilized CLIC1 by inhibiting ubiquitylation. The substitution of K131 inhibited CLIC1 ubiquitylation and promoted cell proliferation, migration, and invasion, and tumor growth. In addition, we identified that acetyltransferase HAT1 was responsible for CLIC1 acetylation at K131. Conclusion: This finding shows that CLIC1 is a tumor promoter in cervical cancer, indicating a potential strategy to treat cervical cancer by regulating CLIC1 expression or acetylation.

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Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers

Cited by 88 publications

References 105 publications

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders

Acetylation stabilizes chloride intracellular channel 1 that exerts a tumor-promoting role by activation of nuclear factor kappa B in cervical cancer

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