bims-meprid 2023-08-20 papers

Issue of 2023‒08‒20
three papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Transl Oncol. 2023 Aug 10. pii: S1936-5233(23)00144-4. [Epub ahead of print]37 101758

Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression.

Madhura R Pandkar, Sommya Sinha, Atul Samaiya, Sanjeev Shukla.

Due to the enhanced glycolytic rate, cancer cells generate lactate copiously, subsequently promoting the lactylation of histones. While previous studies have explored the impact of histone lactylation in modulating gene expression, the precise role of this epigenetic modification in regulating oncogenes is largely unchartered. In this study, using breast cancer cell lines and their mutants exhibiting lactate-deficient metabolome, we have identified that an enhanced rate of aerobic glycolysis supports c-Myc expression via promoter-level histone lactylation. Interestingly, c-Myc further transcriptionally upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing of MDM4 and Bcl-x in breast cancer cells. Moreover, our results reveal that restricting the activity of critical glycolytic enzymes affects the c-Myc-SRSF10 axis to subside the proliferation of breast cancer cells. Our findings provide novel insights into the mechanisms by which aerobic glycolysis influences alternative splicing processes that collectively contribute to breast tumorigenesis. Furthermore, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis.

Keywords: Epigenetics; Histone modifications; SRSF10; Tumor metabolism; Warburg effect; c-Myc

DOI: https://doi.org/10.1016/j.tranon.2023.101758

Carcinogenesis. 2023 Aug 16. pii: bgad058. [Epub ahead of print]

On the road to colorectal cancer development: crosstalk between the gut microbiota, metabolic reprogramming and epigenetic modifications.

Anqi Chen, Zhengting Jiang, Lingli Cai, Dong Tang.

An increasing number of studies have reported the role of gut microbes in colorectal cancer (CRC) development, as they can be influenced by dietary metabolism and mediate alterations in host epigenetics, ultimately affecting CRC. Intake of specific dietary components can affect gut microbial composition and function, and their metabolism regulates important epigenetic functions that may influence CRC risk. Gut microbes can regulate epigenetic modifications through nutrient metabolism, including histone modification, DNA methylation, and noncoding RNAs. Epigenetics, in turn, determines the gut microbial composition and thus influences the risk of developing CRC. This review discusses the complex crosstalk between metabolic reprogramming, gut microbiota, and epigenetics in CRC and highlights the potential applications of the gut microbiota as a biomarker for the prevention, diagnosis, and therapy of CRC.

Keywords: colorectal cancer; epigenetics; gut microbes; metabolic reprogramming; obesity

DOI: https://doi.org/10.1093/carcin/bgad058

Aging Cell. 2023 Aug 18. e13932

ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level.

Shuixin Lv, Yusi Zhang, Yingbin Lin, Wenting Fang, Yu Wang, Zihang Li, Anlan Lin, Xiaoman Dai, Qinyong Ye, Jing Zhang, Xiaochun Chen.

Although aging and apolipoprotein E (APOE) ε4 allele have been documented as two major risk factors for late-onset Alzheimer's disease (LOAD), their interaction and potential underlying mechanisms remain unelucidated. Using humanized ApoE4- and ApoE3- target replacement mice, we found the accumulation of senescent neurons and the activation of mTOR and endosome-lysosome-autophagy (ELA) system in the hippocampus of aged ApoE4 mice. Further analyses revealed that ApoE4 aggravated the profile change of hippocampal transcription and metabolism in an age-dependent manner, accompanying with an disruption of metabolism, which is presented with the downregulating activity of citrate synthase, the level of ATP and, most importantly, the level of acetyl coenzyme A (Ac-CoA); GTA supplement, an Ac-CoA substrate, reversed the senescent characteristics, decreased the activation of mTOR and ELA system, and enhanced the synaptic structure and increasing level of pre-/post-synaptic plasticity-related protein, leading to cognitive improvement in aged ApoE4 mice. These data suggest that ApoE4 exacerbates neuronal senescence due to a deficiency of acetyl-CoA, which can be ameliorated by GTA supplement. The findings provide novel insights into the potential therapeutic value of GTA supplement for the cognitive improvement in aged APOE4 carriers.

Keywords: Alzheimer's disease; ApoE4; acetate; acetyl-CoA; synaptic plasticity

DOI: https://doi.org/10.1111/acel.13932