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茁壮成长的能力取决于对环境中可用营养物质的利用。在这里，我们发现胰腺癌相关成纤维细胞（CAF）通过分泌乙酸盐来调节肿瘤细胞代谢，而乙酸盐的分泌可以通过沉默 CAF 中的 ATP 柠檬酸裂解酶（ACLY）来阻断。我们进一步表明，乙酰辅酶A合成酶短链家族成员2（ACSS2）可引导外源性乙酸盐调节动态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生存。比较 H3K27ac ChIP-seq 和 RNA-seq 分析揭示了通过调节SAT1基因表达和富集SP1响应特征来改变多胺稳态。我们鉴定了醋酸盐/ACSS2 介导的 SP1 在赖氨酸 19 残基处的乙酰化，这增加了 SP1 蛋白的稳定性和转录活性。ACSS2–SP1–SAT1 轴的遗传或药理学抑制可减轻小鼠模型中的肿瘤负担。这些结果表明，基质衍生的乙酸盐赋予的代谢灵活性使癌细胞能够通过 ACSS2-SP1-SAT1 轴在酸中毒下存活。