Abstract
The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP–seq and RNA–seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2–SP1–SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2–SP1–SAT1 axis.
肿瘤细胞在恶劣的微环境中生存的能力依赖于对周围可用营养物质的利用。在这项研究中，我们发现了胰腺癌相关成纤维细胞（CAFs）通过分泌乙酸调节肿瘤细胞代谢，这一过程可以通过沉默CAFs中的ATP柠檬酸裂解酶（ACLY）来阻断。我们进一步研究表明，乙酰辅酶A合成酶短链家族成员2（ACSS2）引导外源乙酸调节癌症表观基因组和转录组，从而促进癌细胞在酸性微环境中的生存。通过比较H3K27ac ChIP-seq和RNA-seq分析，揭示了通过调控SAT1基因表达和富集SP1响应特征而导致的多胺稳态变化。我们发现乙酸/ACSS2介导的SP1在赖氨酸19位残基上的乙酰化增加了SP1蛋白的稳定性和转录活性。对ACSS2–SP1–SAT1轴的基因或药理学抑制在小鼠模型中减少了肿瘤负荷。这些结果揭示了由基质分泌的乙酸赋予的代谢灵活性通过ACSS2–SP1–SAT1轴使癌细胞在酸中毒环境下生存成为可能。
Murthy D, Attri KS, Shukla SK, Thakur R, Chaika NV, He C, Wang D, Jha K, Dasgupta A, King RJ, Mulder SE, Souchek J, Gebregiworgis T, Rai V, Patel R, Hu T, Rana S, Kollala SS, Pacheco C, Grandgenett PM, Yu F, Kumar V, Lazenby AJ, Black AR, Ulhannan S, Jain A, Edil BH, Klinkebiel DL, Powers R, Natarajan A, Hollingsworth MA, Mehla K, Ly Q, Chaudhary S, Hwang RF, Wellen KE, Singh PK. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis. Nat Cell Biol. 2024 Apr;26(4):613-627. doi: 10.1038/s41556-024-01372-4. Epub 2024 Mar 1. Erratum in: Nat Cell Biol. 2024 May;26(5):840. doi: 10.1038/s41556-024-01417-8. PMID: 38429478; PMCID: PMC11021164.
