bims-meprid 2022-11-20 papers

Issue of 2022‒11‒20
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Mol Cell. 2022 Nov 17. pii: S1097-2765(22)01055-3. [Epub ahead of print]82(22): 4246-4261.e11

Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis.

Sujin Park, Dirk Mossmann, Qian Chen, Xueya Wang, Eva Dazert, Marco Colombi, Alexander Schmidt, Brendan Ryback, Charlotte K Y Ng, Luigi M Terracciano, Markus H Heim, Michael N Hall.

Acetyl-coenzyme A (acetyl-CoA) plays an important role in metabolism, gene expression, signaling, and other cellular processes via transfer of its acetyl group to proteins and metabolites. However, the synthesis and usage of acetyl-CoA in disease states such as cancer are poorly characterized. Here, we investigated global acetyl-CoA synthesis and protein acetylation in a mouse model and patient samples of hepatocellular carcinoma (HCC). Unexpectedly, we found that acetyl-CoA levels are decreased in HCC due to transcriptional downregulation of all six acetyl-CoA biosynthesis pathways. This led to hypo-acetylation specifically of non-histone proteins, including many enzymes in metabolic pathways. Importantly, repression of acetyl-CoA synthesis promoted oncogenic dedifferentiation and proliferation. Mechanistically, acetyl-CoA synthesis was repressed by the transcription factors TEAD2 and E2A, previously unknown to control acetyl-CoA synthesis. Knockdown of TEAD2 and E2A restored acetyl-CoA levels and inhibited tumor growth. Our findings causally link transcriptional reprogramming of acetyl-CoA metabolism, dedifferentiation, and cancer.

Keywords: E2A; HCC; TEAD2; acetyl-CoA metabolism; dedifferentiation; hepatocellular carcinoma; protein acetylation; transcriptional reprogramming

DOI: https://doi.org/10.1016/j.molcel.2022.10.027

Front Cell Dev Biol. 2022 ;10 1015125

Elongator promotes neuritogenesis via regulation of tau stability through acly activity.

Michal Shilian, Aviel Even, Hila Gast, Laurent Nguyen, Miguel Weil.

The six subunits (Elp1 to Elp6) Elongator complex promotes specific uridine modifications in tRNA's wobble site. Moreover, this complex has been indirectly involved in the regulation of α-tubulin acetylation in microtubules (MTs) via the stabilization of ATP-Citrate Lyase (Acly), the main cytosolic source of acetyl-CoA production in cells, a key substrate used for global protein acetylation. Here, we report additional evidence that Elongator activity is important for proper cytoskeleton remodeling as cells lacking expression of Elp1 show morphology impairment; including distinct neurite process formation and disorganization and instability of MTs. Here, we show that loss of Elongator results in a reduction of expression of the microtubule associated protein Tau (MAPT). Tau, is a well-known key MT regulator in neurons whose lysines can be competitively acetylated or ubiquitylated. Therefore, we tested whether Tau is an indirect acetylation target of Elongator. We found that a reduction of Elongator activity leads to a decrease of lysine acetylation on Tau that favors its proteasomal degradation. This phenotype was prevented by using selective deacetylase or proteasomal inhibitors. Moreover, our data demonstrate that Acly's activity regulates the mechanism underlying Tau mediated neurite morphology defects found in Elp1 KD since both Tau levels and neurites morphology are restored due to Acly overexpression. This suggests a possible involvement of both Tau and Acly dysfunction in Familial Dysautonomia (FD), which is an autosomal recessive peripheral neuropathy caused by mutation in the ELP1 gene that severely affects Elp1 expression levels in the nervous system in FD patients in a similar way as found previously in Elp1 KD neuroblastoma cells.

Keywords: MAPT/Tau protein; elongator complex; familial dysautonomia; neuritogenesis; protein acetylation

DOI: https://doi.org/10.3389/fcell.2022.1015125

Trends Immunol. 2022 Nov 09. pii: S1471-4906(22)00211-3. [Epub ahead of print]

The NLRP3 inflammasome: regulation by metabolic signals.

Antoni Olona, Stuart Leishman, Paras K Anand.

Macrophages undergo profound metabolic reprogramming upon sensing infectious and sterile stimuli. This metabolic shift supports and regulates essential innate immune functions, including activation of the NLRP3 inflammasome. Within distinct metabolic networks, key enzymes play pivotal roles to control flux restraining detrimental inflammasome signaling. However, depending on the metabolic cues, specific enzymes and metabolites result in inflammasome activation outcomes which contrast other metabolic steps in the pathway. We posit that understanding which metabolic steps commit to discrete inflammasome fates will broaden our understanding of metabolic checkpoints to maintain homeostasis and offer better therapeutic options in human disease.

Keywords: NLRP3; TCA cycle; glycolysis; inflammasome; lipids; metabolism

DOI: https://doi.org/10.1016/j.it.2022.10.003

Biochem Biophys Res Commun. 2022 Nov 11. pii: S0006-291X(22)01562-5. [Epub ahead of print]637 144-152

α-ketoglutarate suppresses immediate early gene expression in cancer cells.

Sungmin Joo, Seungwoo Baek, Jaehyeon Kang, Dong Soo Seo, Taeg Kyu Kwon, Younghoon Jang.

Cancer cells exhibit increased glutamine consumption compared to normal cells, supporting cell survival and proliferation. Glutamine is converted to α-ketoglutarate (αKG), which then enters the tricarboxylic acid cycle to generate ATP. Recently, therapeutic modulation of glutamine metabolism has become an attractive metabolic anti-cancer strategy. However, how synergistic combination therapy is required to overcome glutamine metabolism drug resistance remains elusive. To address this issue, we first investigated the role of αKG in regulating gene expression in several cancer cell lines. Using RNA-seq analysis and histone modification screening, we demonstrated that αKG reduced the expression of the immediate early gene (IEG) in cancer cells in an H3K27 acetylation-dependent manner. Conversely, glutaminase (GLS) inhibitors induce IEG expression in cancer cells. Furthermore, we showed that siRNA knockdown of orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) induces IEG expression. Notably, the NR4A1 agonist cytosporone B sensitizes GLS inhibitor resistance to cancer cell death. Together, these findings indicate that therapeutic targeting of IEG dysregulation by αKG can be a potentially effective anti-cancer therapeutic strategy for glutamine metabolism inhibitors.

Keywords: Cancer cells; GLS inhibitor; IEG; NR4A; αKG

DOI: https://doi.org/10.1016/j.bbrc.2022.11.021

Benef Microbes. 2022 Nov 15. 1-8

Epigenetic regulation by metabolites from the gut microbiome.

C Marín-Tello, P Jintaridth, F Sanchez, C González, L Zelada-Castillo, A Vásquez-Arqueros, A Guevara-Vásquez, A Vieira.

The gut microbiome can metabolise food components, such as dietary fibres and various phytochemicals; and the microbiome can also synthesise some nutrients, for example B vitamins. The metabolites produced by bacteria and other micro-organisms in the colon can have implications for health and disease risk. Some of these metabolites are epigenetically active, and can contribute to changes in the chemical modification and structure of chromatin by affecting the activity and expression of epigenetically-active enzymes, for example histone deacetylases and DNA methyltransferases. The epigenetic activity of such gut microbiome metabolites is reviewed herein.

Keywords: diet; epigenetic; gut; microbiome; nutrition; plant metabolites

DOI: https://doi.org/10.3920/BM2022.0006