Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells

Cencioni, Chiara; Spallotta, Francesco; Savoia, Matteo; Kuenne, Carsten; Guenther, Stefan; Re, Agnese; Wingert, Susanne; Rehage, Maike; Sürün, Duran; Siragusa, Mauro; Smith, Jacob G.; Schnütgen, Frank; Melchner, Harald von; Rieger, Michael A.; Martelli, Fabio; Riccio, Antonella; Fleming, Ingrid; Braun, Thomas; Zeiher, Andreas M.; Farsetti, Antonella

doi:10.1038/s41467-018-03668-0

Cited by 16 publications

(9 citation statements)

References 69 publications

(128 reference statements)

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“…It has been recently reported that miR-200 family expression is controlled by endogenous NO allowing for the mesendodermal differentiation of mouse embryonic stem cells 51 , 52 . miR-200 family is usually down-modulated during tumour progression.…”

Section: Resultsmentioning

confidence: 99%

α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis

et al. 2018

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Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET–miR200–Zeb1/CtBP1–MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.

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Section: Resultsmentioning

confidence: 99%

α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis

et al. 2018

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“…These factors induce EMT-related stem cell properties and promote tumorigenesis via PTMs ( Mani et al, 2008 ; Tam and Weinberg, 2013 ; Ye et al, 2015 ; Dai et al, 2020 ). S-nitrosylation of HDAC2 is regulated by endothelial nitric oxide synthase (eNOS) that is a crucial enzyme for NO synthesis, allowing ZEB1 re-activation ( Cencioni et al, 2018 ). During hypoxia, HDAC3 is essential for the activation of mesenchymal gene expression by the interaction with WD repeat domain 5 (WDR5) ( Wu et al, 2011 ).…”

Section: Biological Functions Of Hdacsmentioning

confidence: 99%

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Guo

Tian

Zhu

2020

Front. Cell Dev. Biol.

199

135

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Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (N ε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

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“…Bl_NOS transcription also reduced with HDACi treatment. NOS is essential for the generation of nitric oxide, which has important roles in pluripotency and immune responses (Beltran-Povea et al, 2015;Cencioni et al, 2018;Lee et al, 2017). Bl_NOS mRNA is expressed in multiple cell types including haemoblasts and the regeneration niche.…”

Section: Changes To Mrna Expression During Wbr Resulting From Hdacimentioning

confidence: 99%

Histone deacetylase activity is required for Botrylloides leachii whole body regeneration

Zondag

Clarke

Wilson

2019

Journal of Experimental Biology

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The colonial tunicate Botrylloides leachii is exceptional at regenerating from a piece of vascular tunic after loss of all adults from the colony. Previous transcriptome analyses indicate a brief period of healing before regeneration of a new adult (zooid) in as little as 8-10 days. However, there is little understanding of how the resulting changes to gene expression, required to drive regeneration, are initiated and how the overall process is regulated. Rapid changes to transcription often occur in response to chromatin changes, mediated by histone modifications such as histone acetylation. Here, we investigated a group of key epigenetic modifiers, histone deacetylases (HDAC), which are known to play an important role in many biological processes such as development, healing and regeneration. Through our transcriptome data, we identified and quantified the expression levels of HDAC and histone acetyltransferase enzymes during wholebody regeneration (WBR). To determine whether HDAC activity is required for WBR, we inhibited its action using valproic acid and trichostatin A. HDAC inhibition prevented the final morphological changes normally associated with WBR and resulted in aberrant gene expression. Botrylloides leachii genes including Slit2, TGF-β, Piwi and Fzd4 all showed altered mRNA levels upon HDAC inhibition in comparison with the control samples. Additionally, atypical expression of Bl_Piwi was found in immunocytes upon HDAC inhibition. Together, these results show that HDAC function, specifically HDAC I/IIa class enzymes, are vital for B. leachii to undergo WBR successfully.

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Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells

Cited by 16 publications

References 69 publications

α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis

α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Histone deacetylase activity is required for Botrylloides leachii whole body regeneration

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