bims-meprid 2023-05-14 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2023–05–14
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation.
Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression.
The short-chain fatty acid acetate coordinates with CD30 to modulate T cell survival.
Acyl-CoA thioesterase 12 suppresses YAP-mediated hepatocarcinogenesis by limiting glycerolipid biosynthesis.
Crucial role of iron in epigenetic rewriting during adipocyte differentiation mediated by JMJD1A and TET2 activity.
Metabolic Reprogramming by Histone Deacetylase Inhibition Selectively Targets NRF2-activated tumors.
Inosine Induces Stemness Features in CAR T cells and Enhances Potency.

Sci Rep. 2023 05 06. 13(1): 7387

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation.

Renee M Mahr, Snehalata Jena, Sereen K Nashif, Alisa B Nelson, Adam J Rauckhorst, Ferrol I Rome, Ryan D Sheldon, Curtis C Hughey, Patrycja Puchalska, Micah D Gearhart, Eric B Taylor, Peter A Crawford, Sarah A Wernimont.

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established BeWo cell culture model of trophoblast differentiation. Differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

DOI: https://doi.org/10.1038/s41598-023-34435-x
J Clin Invest. 2023 May 11. pii: e161713. [Epub ahead of print]

Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression.

Dongmei Gou, Rui Liu, Xiaoqun Shan, Haijun Deng, Chang Chen, Jin Xiang, Yi Liu, Qingzhu Gao, Zhi Li, Ailong Huang, Kai Wang, Ni Tang.

  Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency-induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 knockout in vivo and in vitro. These findings reveal the availability of key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC.

Keywords:  Gluconeogenesis; Liver cancer; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI161713
Mol Biol Cell. 2023 May 10. mbcE23010032

The short-chain fatty acid acetate coordinates with CD30 to modulate T cell survival.

Junfang Lyu, Ziyi Li, Jessica Roberts, Yue A Qi, Jianhua Xiong.

As an important substrate for cell metabolism, the short-chain fatty acid acetate emerges as a regulator of cell fate and function. However, its role in T cell survival and its underlying mechanisms remain largely unknown. Here, we demonstrate that acetate modulates T cell apoptosis via potentiation of α-tubulin acetylation. We further show that acetate treatment effectively increases the expression of the tumor necrosis factor receptor (TNFR) family member CD30 by enhancing its gene transcription. Moreover, CD30 physically associates with and stabilizes the deacetylase HDAC6, which deacetylates α-tubulin to decrease microtubule stability. Proteomic profiling of Cd30 knockout (Cd30-/-) T cells reveals elevated expression of anti-apoptotic BCL2 family proteins and thus promotes T cell survival via a microtubule-Bcl-2 axis. Taken together, our results demonstrate that acetate is a regulator of T cell survival by controlling levels of acetylated α-tubulin. This suggests that therapeutic manipulation of acetate metabolism may facilitate optimal T cell responses in pathological conditions.

DOI: https://doi.org/10.1091/mbc.E23-01-0032
Cancer Lett. 2023 May 05. pii: S0304-3835(23)00161-1. [Epub ahead of print] 216210

Acyl-CoA thioesterase 12 suppresses YAP-mediated hepatocarcinogenesis by limiting glycerolipid biosynthesis.

Haiyue He, Akiko Sugiyama, Nathaniel W Snyder, Marcos G Teneche, Xiaowei Liu, Kristal M Maner-Smith, Wolfram Goessling, Susan J Hagen, Eric A Ortlund, S Hani Najafi-Shoushtari, Mariana Acuña, David E Cohen.

  Cancer cells use acetate to support the higher demand for energy and lipid biosynthesis during uncontrolled cell proliferation, as well as for acetylation of regulatory proteins. Acyl-CoA thioesterase 12 (Acot12) is the enzyme that hydrolyzes acetyl-CoA to acetate in liver cytosol and is downregulated in hepatocellular carcinoma. A mechanistic role for Acot12 in hepatocarcinogenesis was assessed in mice in response to treatment with diethylnitrosamine/carbon tetrachloride administration or prolonged feeding of a diet that promotes non-alcoholic steatohepatitis. Relative to controls, Acot12-/- mice exhibited accelerated liver tumor formation that was characterized by the hepatic accumulation of glycerolipids, including lysophosphatidic acid (LPA), and that was associated with reduced Hippo signaling and increased YAP-mediated transcriptional activity. In Acot12-/- mice, restoration of hepatic Acot12 expression inhibited hepatocarcinogenesis and YAP activation, as did knockdown of hepatic YAP expression. Excess LPA produced due to deletion of Acot12 signaled through LPA receptors coupled to Gα12/13 subunits to suppress YAP phosphorylation, thereby promoting its nuclear localization and transcriptional activity. These findings identify a protective role for Acot12 in suppressing hepatocarcinogenesis by limiting biosynthesis of glycerolipids including LPA, which preserves Hippo signaling.

Keywords:  Acetate; Acetyl-CoA; Hepatocellular carcinoma; Hippo pathway; Lysophosphatidic acid

DOI:  https://doi.org/10.1016/j.canlet.2023.216210
Nucleic Acids Res. 2023 May 09. pii: gkad342. [Epub ahead of print]

Crucial role of iron in epigenetic rewriting during adipocyte differentiation mediated by JMJD1A and TET2 activity.

Tomohiro Suzuki, Tetsuro Komatsu, Hiroshi Shibata, Akiko Tanioka, Diana Vargas, Reika Kawabata-Iwakawa, Fumihito Miura, Shinnosuke Masuda, Mayuko Hayashi, Kyoko Tanimura-Inagaki, Sumiyo Morita, Junki Kohmaru, Koji Adachi, Masayuki Tobo, Hideru Obinata, Tasuku Hirayama, Hiroshi Kimura, Juro Sakai, Hideko Nagasawa, Hideyuki Itabashi, Izuho Hatada, Takashi Ito, Takeshi Inagaki.

Iron metabolism is closely associated with the pathogenesis of obesity. However, the mechanism of the iron-dependent regulation of adipocyte differentiation remains unclear. Here, we show that iron is essential for rewriting of epigenetic marks during adipocyte differentiation. Iron supply through lysosome-mediated ferritinophagy was found to be crucial during the early stage of adipocyte differentiation, and iron deficiency during this period suppressed subsequent terminal differentiation. This was associated with demethylation of both repressive histone marks and DNA in the genomic regions of adipocyte differentiation-associated genes, 　including Pparg, which encodes PPARγ, the master regulator of adipocyte differentiation. In addition, we identified several epigenetic demethylases to be responsible for iron-dependent adipocyte differentiation, with the histone demethylase jumonji domain-containing 1A and the DNA demethylase ten-eleven translocation 2 as the major enzymes. The interrelationship between repressive histone marks and DNA methylation was indicated by an integrated genome-wide association analysis, and was also supported by the findings that both histone and DNA demethylation were suppressed by either the inhibition of lysosomal ferritin flux or the knockdown of iron chaperone poly(rC)-binding protein 2. In summary, epigenetic regulations through iron-dependent control of epigenetic enzyme activities play an important role in the organized gene expression mechanisms of adipogenesis.

DOI: https://doi.org/10.1093/nar/gkad342
bioRxiv. 2023 Apr 28. pii: 2023.04.24.538118. [Epub ahead of print]

Metabolic Reprogramming by Histone Deacetylase Inhibition Selectively Targets NRF2-activated tumors.

Dimitris Karagiannis, Warren Wu, Albert Li, Makiko Hayashi, Xiao Chen, Michaela Yip, Vaibhav Mangipudy, Xinjing Xu, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano, Jiangbin Ye, Thales Papagiannakopoulos, Chao Lu.

Interplay between metabolism and chromatin signaling have been implicated in cancer initiation and progression. However, whether and how metabolic reprogramming in tumors generates specific epigenetic vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor mutations that cause aberrant activation of the NRF2 antioxidant pathway and drive aggressive and chemo-resistant disease. We performed a chromatin-focused CRISPR screen and report that NRF2 activation sensitized LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association was consistently observed across cultured cells, syngeneic mouse models and patient-derived xenografts. HDAC inhibition causes widespread increases in histone H4 acetylation (H4ac) at intergenic regions, but also drives re-targeting of H4ac reader protein BRD4 away from promoters with high H4ac levels and transcriptional downregulation of corresponding genes. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that these chromatin changes are associated with reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest that metabolic alterations such as NRF2 activation could serve as biomarkers for effective repurposing of HDAC inhibitors to treat solid tumors.

DOI: https://doi.org/10.1101/2023.04.24.538118
bioRxiv. 2023 Apr 25. pii: 2023.04.21.537859. [Epub ahead of print]

Inosine Induces Stemness Features in CAR T cells and Enhances Potency.

Dorota D Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A Freitas, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Amaury Leruste, Malek Bashti, Vimal Keerthi, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L Davis, Ansuman T Satpathy, Steven A Feldman, Elena Sotillo, Crystal L Mackall.

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 + CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
Statement of Significance: Adenosine is well known to inhibit T cell function and substantial effort has focused on inhibiting adenosine generation and signaling. Here, we show that exhausted T cells are suppressed by adenosine, which is only modestly impacted by inhibiting adenosine generation or signaling. In contrast, metabolism of adenosine to inosine augmented T cell function and culture of T cells with inosine induced multi-level reprogramming leading to stemness and improved anti-tumor potency. We demonstrate the feasibility of introducing inosine during GMP cell manufacturing as a novel strategy to generate enhanced CAR-T cells.

DOI: https://doi.org/10.1101/2023.04.21.537859