bims-meprid 2023-04-16 papers

Issue of 2023‒04‒16
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Cell Prolif. 2023 Apr 14. e13478

Lactate-induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer.

Ting Wang, Zeng Ye, Zheng Li, De-Sheng Jing, Gui-Xiong Fan, Meng-Qi Liu, Qi-Feng Zhuo, Shun-Rong Ji, Xian-Jun Yu, Xiao-Wu Xu, Yi Qin.

Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the 'lactate shuttle' moving between cells and transmitting signals. The glycolytic-dependent metabolism found in tumours and fast-growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate-induced lactylation moves even further on pro-tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone.

DOI: https://doi.org/10.1111/cpr.13478

iScience. 2023 Apr 21. 26(4): 106425

Asparagine starvation suppresses histone demethylation through iron depletion.

Jie Jiang, Sankalp Srivastava, Sheng Liu, Gretchen Seim, Rodney Claude, Minghua Zhong, Sha Cao, Utpal Davé, Reuben Kapur, Amber L Mosley, Chi Zhang, Jun Wan, Jing Fan, Ji Zhang.

Intracellular α-ketoglutarate is an indispensable substrate for the Jumonji family of histone demethylases (JHDMs) mediating most of the histone demethylation reactions. Since α-ketoglutarate is an intermediate of the tricarboxylic acid cycle and a product of transamination, its availability is governed by the metabolism of several amino acids. Here, we show that asparagine starvation suppresses global histone demethylation. This process is neither due to the change of expression of histone-modifying enzymes nor due to the change of intracellular levels of α-ketoglutarate. Rather, asparagine starvation reduces the intracellular pool of labile iron, a key co-factor for the JHDMs to function. Mechanistically, asparagine starvation suppresses the expression of the transferrin receptor to limit iron uptake. Furthermore, iron supplementation to the culture medium restores histone demethylation and alters gene expression to accelerate cell death upon asparagine depletion. These results suggest that suppressing iron-dependent histone demethylation is part of the cellular adaptive response to asparagine starvation.

Keywords: Biological sciences; Epigenetics; Molecular biology; Molecular mechanism of gene regulation; Physiology

DOI: https://doi.org/10.1016/j.isci.2023.106425

Elife. 2023 Apr 13. pii: e81717. [Epub ahead of print]12

PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence.

Michael Xiao, Chia-Hua Wu, Graham Meek, Brian Kelly, Dara Buendia Castillo, Lyndsay E A Young, Sara Martire, Sajina Dhungel, Elizabeth McCauley, Purbita Saha, Altair L Dube, Matthew S Gentry, Laura A Banaszynski, Ramon C Sun, Chintan K Kikani.

Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mitochondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PASK, resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity, and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK.

Keywords: cell biology; human; mouse

DOI: https://doi.org/10.7554/eLife.81717