bims-meprid 2020-10-25 papers

Issue of 2020‒10‒25
four papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Trends Cell Biol. 2020 Oct 19. pii: S0962-8924(20)30190-2. [Epub ahead of print]

Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases.

Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of α-ketoglutarate (αKG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. αKG-dependent dioxygenases consume the metabolite αKG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via αKG-dependent dioxygenases.

Keywords: 2-hydroxyglutarate; alpha-ketoglutarate; cell fate; chromatin modifications; succinate; αKG-dependent dioxygenases

DOI: https://doi.org/10.1016/j.tcb.2020.09.010

Nat Rev Cancer. 2020 Oct 21.

2-Oxoglutarate-dependent dioxygenases in cancer.

Julie-Aurore Losman, Peppi Koivunen, William G Kaelin.

2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.

DOI: https://doi.org/10.1038/s41568-020-00303-3

Nat Metab. 2020 Oct 19.

Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.

Lisa Maria Koch, Eivind Salmorin Birkeland, Stefania Battaglioni, Xiao Helle, Mayura Meerang, Stefanie Hiltbrunner, Alfredo J Ibáñez, Matthias Peter, Alessandra Curioni-Fontecedro, Isabelle Opitz, Reinhard Dechant.

Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.

DOI: https://doi.org/10.1038/s42255-020-00297-0

Metab Brain Dis. 2020 Oct 24.

Administration of branched-chain amino acids alters epigenetic regulatory enzymes in an animal model of Maple Syrup Urine Disease.

Emilio L Streck, Felipe P Bussular, Leticia B Wessler, Mariane B Duarte, Victoria L Rezende, Matheus S Rodrigues, Carolina A Torres, Isabela S Lemos, Gabriela Candiotto, Fernanda F Gava, Jade de Oliveira, Samira S Valvassori.

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder that affects the activity of the branched-chainα-keto acid dehydrogenase complex (BCDK). This deficiency on BCDK complex results in the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine, and their corresponding α-keto acids. Epigenetic changes can negatively affect the metabolism of BCAA. These changes are catalyzed by the epigenetic regulatory enzymes, e.g., DNA methyltransferase (DNMT), histone deacetylases (HDAC), and histone acetyltransferases (HAT). However, the impacts of BCAA administration on the activity of epigenetic regulatory enzymes in the brain of MSUD patients are still unknown. In this study, we aimed to demonstrate the impact of BCAA administration on the activity of DNMT, HDAC, and HAT in the brain structures of infant rats, an animal model of MSUD. For that, we administered a BCAA pool to infant rats for 21 days. We demonstrated that BCAA administration significantly increased the DNMT and HDAC activities in the hippocampus and striatum, but not in the cerebral cortex of MSUD infant rats. A positive correlation was observed between HDAC and DNMT activities in the hippocampus and striatum of animals exposed to BCAA injections. Our results showed that the BCAA administration could modulate epigenetic regulatory enzymes, mainly DNMT and HDAC, in the brains of infant rats. Therefore, we suggest that the increase in the activity of DNMT and HDAC in the hippocampus and striatum could partially explain the neurological impairments presented in animal models of MSUD.

Keywords: Branched-chain amino acids; DNA methyltransferase; Epigenetics; Histone acetyltransferases; Histone deacetylases; Maple Syrup Urine Disease

DOI: https://doi.org/10.1007/s11011-020-00631-1