bims-meprid 2023-10-01 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2023–10–01
eight papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Coordination of cross-talk between metabolism and epigenetic regulation by the SIN3 complex.
Iron drives anabolic metabolism through active histone demethylation and mTORC1.
The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation.
Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis.
Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation.
D-2-hydroxyglutarate regulates human brain vascular endothelial cell proliferation and barrier function.
The signalling lipid PI3,5P2 is essential for timely mitotic exit.

Enzymes. 2023 ;pii: S1874-6047(23)00006-9. [Epub ahead of print]53 33-68

Coordination of cross-talk between metabolism and epigenetic regulation by the SIN3 complex.

Imad Soukar, Anjalie Amarasinghe, Lori A Pile.

  Post-translational modifications of histone proteins control the expression of genes. Metabolites from central and one-carbon metabolism act as donor moieties to modify histones and regulate gene expression. Thus, histone modification and gene regulation are connected to the metabolite status of the cell. Histone modifiers, such as the SIN3 complex, regulate genes involved in proliferation and metabolism. The SIN3 complex contains a histone deacetylase and a histone demethylase, which regulate the chromatin landscape and gene expression. In this chapter, we review the cross-talk between metabolic pathways that produce donor moieties, and epigenetic complexes regulating proliferation and metabolic genes. This cross-talk between gene regulation and metabolism is tightly controlled, and disruption of this cross-talk leads to metabolic diseases. We discuss promising therapeutics that directly regulate histone modifiers, and can affect the metabolic status of the cell, alleviating some metabolic diseases.

Keywords:  Diabetes; Epigenetics; Histone deacetylase; Histone demethylase; Metabolism; SIN3; Therapeutics; Transcription

DOI:  https://doi.org/10.1016/bs.enz.2023.06.001
Nat Cell Biol. 2023 Sep 25.

Iron drives anabolic metabolism through active histone demethylation and mTORC1.

Jason S Shapiro, Hsiang-Chun Chang, Yuki Tatekoshi, Zibo Zhao, Zohra Sattar Waxali, Bong Jin Hong, Haimei Chen, Justin A Geier, Elizabeth T Bartom, Adam De Jesus, Farnaz K Nejad, Amir Mahmoodzadeh, Tatsuya Sato, Lucia Ramos-Alonso, Antonia Maria Romero, Maria Teresa Martinez-Pastor, Shang-Chuan Jiang, Shiv K Sah-Teli, Liming Li, David Bentrem, Gary Lopaschuk, Issam Ben-Sahra, Thomas V O'Halloran, Ali Shilatifard, Sergi Puig, Joy Bergelson, Peppi Koivunen, Hossein Ardehali.

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

DOI: https://doi.org/10.1038/s41556-023-01225-6
Adv Sci (Weinh). 2023 Sep 26. e2301939

The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation.

Dina Baier, Theresa Mendrina, Beatrix Schoenhacker-Alte, Christine Pirker, Thomas Mohr, Mate Rusz, Benedict Regner, Martin Schaier, Nicolas Sgarioto, Noël J-M Raynal, Karin Nowikovsky, Wolfgang M Schmidt, Petra Heffeter, Samuel M Meier-Menches, Gunda Koellensperger, Bernhard K Keppler, Walter Berger.

  The leading first-in-class ruthenium-complex BOLD-100 currently undergoes clinical phase-II anticancer evaluation. Recently, BOLD-100 is identified as anti-Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD-100-resistant colon and pancreatic carcinoma cells. Acute BOLD-100 treatment reduces lipid droplet contents of BOLD-100-sensitive but not -resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD-100-resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame-shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl-coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell-free BOLD-100-CoA adduct formation suggesting acetyl-CoA depletion as mechanism bridging BOLD-100-induced lipid metabolism alterations and histone acetylation-mediated gene expression deregulation. Indeed, BOLD-100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de-acetylation as central mode-of-action of BOLD-100 and metabolic programs stabilizing histone acetylation as relevant Achilles' heel of acquired BOLD-100-resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD-100 responsiveness. Summarizing, BOLD-100 is identified as epigenetically active substance acting via targeting several onco-metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD-100 resistance opens novel strategies to tackle therapy failure.

Keywords:  BOLD-100; chemoresistance; histone acetylation; lactate transporter; lipid metabolism; mitochondrial respiration; ruthenium

DOI:  https://doi.org/10.1002/advs.202301939
Adv Sci (Weinh). 2023 Sep 26. e2301300

Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis.

Jinhui Wu, Miao Hu, Heng Jiang, Jun Ma, Chong Xie, Zheng Zhang, Xin Zhou, Jianquan Zhao, Zhengbo Tao, Yichen Meng, Zhuyun Cai, Tengfei Song, Chenglin Zhang, Rui Gao, Chang Cai, Hongyuan Song, Yang Gao, Tao Lin, Ce Wang, Xuhui Zhou.

  Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.

Keywords:  histone lactylation; lactate; metabolic reprogramming; osteoporosis; vascular metabolism

DOI:  https://doi.org/10.1002/advs.202301300
Nat Cell Biol. 2023 Sep 28.

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.

Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.

DOI: https://doi.org/10.1038/s41556-023-01244-3
J Exp Clin Cancer Res. 2023 Sep 29. 42(1): 253

Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation.

Ting Sun, Bin Liu, Yanyan Li, Jie Wu, Yufei Cao, Shuangyu Yang, Huiling Tan, Lize Cai, Shiqi Zhang, Xinyue Qi, Dingjia Yu, Wei Yang.

   BACKGROUND: Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored.
METHODS: Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages.
RESULTS: Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation.
CONCLUSIONS: Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy.

Keywords:  CAR-T; CCR8; Ectonucleotidases; Glioblastoma; Histone lactylation

DOI:  https://doi.org/10.1186/s13046-023-02815-w
J Neuropathol Exp Neurol. 2023 Sep 22. pii: nlad072. [Epub ahead of print]

D-2-hydroxyglutarate regulates human brain vascular endothelial cell proliferation and barrier function.

Chuan Cao, Lingjun Zhang, Mia D Sorensen, Guido Reifenberger, Bjarne W Kristensen, Thomas M McIntyre, Feng Lin.

  Gain-of-function mutations in isocitrate dehydrogenase (IDH) genes result in excessive production of (D)-2-hydroxyglutarate (D-2HG) which intrinsically modifies tumor cell epigenetics and impacts surrounding noncancerous cells through nonepigenetic pathways. However, whether D-2HG has a paracrine effect on endothelial cells in the tumor microenvironment needs further clarification. We quantified microvessel density by immunohistochemistry using tissue sections from 60 high-grade astrocytic gliomas with or without IDH mutation. Microvessel density was found to be reduced in tumors carrying an IDH mutation. Ex vivo experiments showed that D-2HG inhibited endothelial cell migration, wound healing, and tube formation by suppressing cell proliferation but not viability, possibly through reduced activation of the mTOR/STAT3 pathway. Further, D-2HG reduced fluorescent dextran permeability and decreased paracellular T-cell transendothelial migration by augmenting expression of junctional proteins thereby collectively increasing endothelial barrier function. These results indicate that D-2HG may influence the tumor vascular microenvironment by reducing the intratumoral vasculature density and by inhibiting the transport of metabolites and extravasation of circulating cells into the astrocytoma microenvironment. These observations provide a rationale for combining IDH inhibition with antitumor immunological/angiogenic approaches and suggest a molecular basis for resistance to antiangiogenic drugs in patients whose tumors express a mutant IDH allele.

Keywords:  (D)-2-hydroxyglutarate (D-2HG); Astrocytic glioma; Brain vascular endothelial cell; Glioblastoma; Isocitrate dehydrogenase (IDH); Microvascular proliferation

DOI:  https://doi.org/10.1093/jnen/nlad072
Open Biol. 2023 Sep;13(9): 230125

The signalling lipid PI3,5P2 is essential for timely mitotic exit.

Mariam Huda, Seyma Nur Bektas, Baris Bekdas, Ayse Koca Caydasi.

  Coordination of mitotic exit with chromosome segregation is key for successful mitosis. Mitotic exit in budding yeast is executed by the mitotic exit network (MEN), which is negatively regulated by the spindle position checkpoint (SPOC). SPOC kinase Kin4 is crucial for SPOC activation in response to spindle positioning defects. Here, we report that the lysosomal signalling lipid phosphatidylinositol-3,5-bisphosphate (PI3,5P2) has an unanticipated role in the timely execution of mitotic exit. We show that the lack of PI3,5P2 causes a delay in mitotic exit, whereas elevated levels of PI3,5P2 accelerates mitotic exit in mitotic exit defective cells. Our data indicate that PI3,5P2 promotes mitotic exit in part through impairment of Kin4. This process is largely dependent on the known PI3,5P2 effector protein Atg18. Our work thus uncovers a novel link between PI3,5P2 and mitotic exit.

Keywords:  PI3; mitosis; mitotic exit; mitotic exit network; phosphoinositide; signalling lipid

DOI:  https://doi.org/10.1098/rsob.230125