bims-meprid 2024-11-10 papers

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2024–11–10
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia.
ACAT1 Induces the Differentiation of Glioblastoma Cells by Rewiring Choline Metabolism.

Nat Cell Biol. 2024 Nov 06.

NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia.

Subo Zhang, Feng Huang, Yushuai Wang, Yifei Long, Yuanpei Li, Yalin Kang, Weiwei Gao, Xiuxin Zhang, Yueting Wen, Yun Wang, Lili Pan, Youmei Xia, Zhoutian Yang, Ying Yang, Hongjie Mo, Baiqing Li, Jiacheng Hu, Yunda Song, Shilin Zhang, Shenghua Dong, Xiao Du, Yingmin Li, Yadi Liu, Wenting Liao, Yijun Gao, Yaojun Zhang, Hongming Chen, Yang Liang, Jianjun Chen, Hengyou Weng, Huilin Huang.

RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy.

DOI: https://doi.org/10.1038/s41556-024-01548-y
Int J Biol Sci. 2024 ;20(14): 5576-5593

ACAT1 Induces the Differentiation of Glioblastoma Cells by Rewiring Choline Metabolism.

Shen You, Ming-Jin Wang, Zhen-Yan Hou, Wei-Da Wang, Zhi-Hui Zhang, Ting-Ting Du, Shu-Ying Li, Yi-Chen Liu, Ni-Na Xue, Xiao-Min Hu, Xiao-Guang Chen, Ming Ji.

  Abnormal differentiation of cells is a hallmark of malignancy. Induction of cancer-cell differentiation is emerging as a novel therapeutic strategy with low toxicity in hematological malignances, but whether such treatment can be used in solid tumors is not known. Here, we uncovered a novel function of acetyl coenzyme A acetyltransferase (ACAT1) in regulating the differentiation of glioblastoma (GBM) cells. Inhibition of ACAT1 promoted the differentiation of GBM cells into astrocytes but also delayed tumor growth. Mechanistically, suppression of ACAT1 restored mitochondrial function and led to metabolic "reprogramming" in GBM cells: reduction of fatty-acid oxidation and acetyl-CoA, but an increase in free fatty acids. Importantly, ACAT1 negatively regulated the choline metabolic pathway, which is crucial for the differentiation of GBM cells. Finally, we demonstrated that a naturally available substance, chlorogenic acid (CHA), could inhibit phosphorylation of ACAT1 and so delay GBM progression, CHA is a promising candidate to treat GBM because it could induce the differentiation of cancer cells.

Keywords:  acetyl coenzyme A acetyltransferase; cell differentiation; choline; glioblastoma

DOI:  https://doi.org/10.7150/ijbs.96651