An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma

Ooi, Aikseng; Wong, Jing Chii; Petillo, David; Roossien, Douglas H.; Perrier-Trudova, Victoria; Whitten, Douglas; Min, Bernice Wong Hui; Tan, Min; Zhang, Zhongfa; Yang, Ximing J.; Zhou, Ming; Gardie, Betty; Molinié, Vincent; Richard, Stéphane; Tan, Puay Hoon; Teh, Bin Tean; Furge, Kyle A.

doi:10.1016/j.ccr.2011.08.024

Cited by 364 publications

(328 citation statements)

References 62 publications

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“…Collectively, these findings support the notion that AA is capable of functioning as a signaling molecule in regulating muscle cell function. Interestingly, recent reports have demonstrated that abnormally accumulated fumarate plays a novel role in the irregular modification of cellular proteins (succination of KEAP1) and Nrf2 (NFE2-related factor 2) signaling in fumarate hydratase-deficient cells and that these functions are independent of its ability to inhibit ␣-ketoglutarate-dependent dioxygenases (17,(73)(74)(75). Thus, our findings and the results of prior studies collectively indicate that AA could regulate cellular activity independent of its energetic role.…”

Section: Discussionsupporting

confidence: 71%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

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Section: Discussionsupporting

confidence: 71%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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“…In this study, we found that the NRF2 signaling pathway was the single most significantly dysregulated pathway in leiomyomas of the FH subtype, whereas the HIF1α signaling pathway was not significantly altered. We detected AKR1B10, a known target of NRF2 (29), as a highly promising biomarker for FH deficiency. NRF2 activation has previously been shown to redirect glucose and glutamine into anabolic pathways, including the pentose phosphate pathway (31).…”

Section: Discussionmentioning

confidence: 97%

“…The NRF2-mediated oxidative stress response was the most significantly dysregulated pathway in leiomyomas of the FH subtype (Table S1). Furthermore, 8 of the 20 most uniquely expressed genes (AKR1B10, TKT, PIR, SLC7A11, NQO1, SRXN1, SLC6A6, and GCLM) have previously been reported as targets of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) (28)(29)(30)(31). The pentose phosphate pathway was the only other statistically significant pathway, and three (TKT, PGD, and G6PD) of the 20 most uniquely expressed genes encode for key enzymes of this pathway.…”

Section: Unsupervised Hierarchical Clustering Reveals Distinct Expresmentioning

confidence: 99%

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

Mehine

Kaasinen

Heinonen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

190

231

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Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/β-catenin, Prolactin, and insulin-like growth factor (IGF)1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.uterine leiomyoma | transcriptional profiling | MED12 | HMGA2

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“…In parallel to succinate, fumarate has been shown to competitively inhibit αKG‐dependent dioxygenase enzymes, resulting in a pseudohypoxic transcriptome through HIFα stabilization76 and a hypermethylator phenotype 76, 77. However, contrary to initial thoughts, now there is evidence to suggest that stabilization of HIF is not the driver of tumorigenesis in FH‐deficient tumors, and that a different candidate transcription factor—the nuclear‐related factor 2 (NRF2) pathway—may instead be involved 78, 79…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Hollinshead

Tennant

2016

WIREs Mechanisms of Disease

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Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334For further resources related to this article, please visit the WIREs website.

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An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma

Cited by 364 publications

References 62 publications

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

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