bims-meprid 2023-12-10 papers

bioRxiv. 2023 Nov 22. pii: 2023.11.22.568331. [Epub ahead of print]

Methionine availability influences essential H3K36me3 dynamics during cell differentiation.

Yudong Sun, Vijyendra Ramesh, Fangchao Wei, Jason W Locasale.

Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2. Methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.

DOI: https://doi.org/10.1101/2023.11.22.568331

PLoS One. 2023 ;18(12): e0293676

Lactate-induced histone lactylation by p300 promotes osteoblast differentiation.

Erika Minami, Kiyohito Sasa, Atsushi Yamada, Ryota Kawai, Hiroshi Yoshida, Haruhisa Nakano, Koutaro Maki, Ryutaro Kamijo.

Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.

DOI: https://doi.org/10.1371/journal.pone.0293676

Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00415-1. [Epub ahead of print]35(12): 2093-2094

Fructose sweetens the adipocyte-T cell alliance against tumors.

Peipei Zhou, Hongbo Chi.

Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang et al. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ T cells for improved tumor control.

DOI: https://doi.org/10.1016/j.cmet.2023.11.004

Sci Adv. 2023 Dec 08. 9(49): eadi2465

Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation.

Wei Xiang, Hongwei Lv, Fuxue Xing, Xiaoyan Sun, Yue Ma, Lu Wu, Guishuai Lv, Qianni Zong, Liang Wang, Zixin Wu, Qiyu Feng, Wen Yang, Hongyang Wang.

Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.

DOI: https://doi.org/10.1126/sciadv.adi2465