bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒04‒18
six papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Front Oncol. 2021 ;11 619300
      Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.
    Keywords:  HIF-1; IDH; PHD; TET; ascorbate; brain cancer; hypoxia
  2. Cell Death Dis. 2021 Apr 15. 12(4): 408
      One of the malignant transformation hallmarks is metabolism reprogramming, which plays a critical role in the biosynthetic needs of unchecked proliferation, abrogating cell death programs, and immunologic escape. However, the mechanism of the metabolic switch is not fully understood. Here, we found that the S-nitrosoproteomic profile of endogenous nitrogen oxide in ovarian cancer cells targeted multiple components in metabolism processes. Phosphofructokinase (PFKM), one of the most important regulatory enzymes of glycolysis, was S-nitrosylated by nitric oxide synthase NOS1 at Cys351. S-nitrosylation at Cys351 stabilized the tetramer of PFKM, leading to resist negative feedback of downstream metabolic intermediates. The PFKM-C351S mutation decreased the proliferation rate of cultured cancer cells, and reduced tumor growth and metastasis in the mouse xenograft model. These findings indicated that S-nitrosylation at Cys351 of PFKM by NOS1 contributes to the metabolic reprogramming of ovarian cancer cells, highlighting a critical role of endogenous nitrogen oxide on metabolism regulations in tumor progression.
  3. Biomed Res. 2021 ;42(2): 85-88
      Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in the biosynthesis of monounsaturated fatty acids, and the expression of the Scd1 gene is induced by the intake of the lipogenic sugar fructose. We examined the effects of a high-fructose diet on hepatic acetylation of histones H3 and H4 and the binding of carbohydrate response element-binding protein (ChREBP) on the Scd1 gene promoter in rats. Rats were fed a control diet or a high-fructose diet for 10 days. The intake of a high-fructose diet significantly increased histone H3 and H4 acetylation and ChREBP binding to the Scd1 gene promoter as well as the amount of triglyceride and the expression of the Scd1 gene. These results suggest that short-term intake of high fructose upregulates expression of Scd1 by enhancing acetylation of histones H3 and H4 and binding of ChREBP at the Scd1 promoter.
  4. Stem Cell Res Ther. 2021 Apr 14. 12(1): 240
      BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is a risk factor for ischemic and hypertensive kidney disease (HKD) for which autologous mesenchymal stem cell (MSC) appears to be a promising therapy. However, MSCs from ARAS patients exhibit impaired function, senescence, and DNA damage, possibly due to epigenetic mechanisms. Hypoxia preconditioning (HPC) exerts beneficial effects on cellular proliferation, differentiation, and gene and protein expression. We hypothesized that HPC could influence MSC function and senescence in ARAS by epigenetic mechanisms and modulating gene expression of chromatin-modifying enzymes.METHODS: Adipose-derived MSC harvested from healthy control (N = 8) and ARAS (N = 8) pigs were cultured under normoxia (20%O2) or hypoxia (1%O2) conditions. MSC function was assessed by migration, proliferation, and cytokine release in conditioned media. MSC senescence was evaluated by SA-β-gal activity. Specific pro-angiogenic and senescence genes were assessed by reverse transcription polymerase chain reaction (RT-PCR). Dot blotting was used to measure global genome 5-hydroxymethylcytosine (5hmC) levels on DNA and Western blotting of modified histone 3 (H3) proteins to quantify tri-methylated lysine-4 (H3K4me3), lysine-9 (H3K9me3), and lysine-27 (H3K27me3) residues.
    RESULTS: Specific pro-angiogenic genes in ARAS assessed by RT-PCR were lower at baseline but increased under HPC, while pro-senescence genes were higher in ARAS at baseline as compared healthy MSCs. ARAS MSCs under basal conditions, displayed higher H3K4me3, H3K27me3, and 5hmC levels compared to healthy MSCs. During HPC, global 5hmC levels were decreased while no appreciable changes occurred in histone H3 tri-methylation. ARAS MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased vascular endothelial growth factor and epidermal growth factor expression compared to normoxia, and SA-β-gal activity decreased in both animal groups.
    CONCLUSIONS: These data demonstrate that swine ARAS MSCs have decreased angiogenesis and increased senescence compared to healthy MSCs and that HPC mitigates MSC dysfunction, senescence, and DNA hydroxymethylation in ARAS MSC. Thus, HPC for MSCs may be considered for their optimization to improve autologous cell therapy in patients with nephropathies.
    Keywords:  Adipose mesenchymal stromal cells; Angiogenesis; Atherosclerotic renal artery stenosis; Chromatin organization; Epigenetics; Hydroxymethylation; Hypoxia; Mesenchymal stem cells; Senescence
  5. Cell Mol Immunol. 2021 Apr 13.
      A mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.
    Keywords:  B cells; CD8; Dietary fiber; Innate lymphoid cells; Microbial metabolites; Microbiota; Short-chain fatty acids; Th1; Th17; Tregs
  6. Exp Dermatol. 2021 Apr 12.
      With the aging of the population and increased levels of recreational sun exposure and immunosuppression, cutaneous squamous cell carcinoma (cSCC), is both an enormous and expanding clinical and economic issue. Despite advances in therapy, up to 5,000-8,000 people are estimated to die every year from cSCC in the U.S., highlighting the need for both better prevention and treatments. Two emerging areas of scientific discovery that may offer new therapeutic approaches for cSCC are epigenetics and metabolism. Importantly, these disciplines display extensive crosstalk, with metabolic inputs contributing to the chromatin landscape, while the dynamic epigenome shapes transcriptional and cellular responses that feedback into cellular metabolism. Recent evidence suggests that indeed, epigenetic and metabolic dysregulation may be critical contributors to cSCC pathogenesis. Here, we synthesize the latest findings from these fast-moving fields, including how they may drive cSCC, yet also be harnessed for therapy.
    Keywords:  Epigenetics; cancer; cutaneous squamous cell carcinoma; metabolism