越来越多的证据表明，暴露于持久性有机污染物（POPs）与各种癌症的发病率和侵袭性增加之间存在因果关系。在这些POPs中，二恶英和PCB-153广泛存在于我们的环境中，并且是重要的污染源。二恶英暴露已与非何杰金淋巴瘤等癌症有关，但在其他癌症中的研究尚需进一步深入。二恶英和PCB-153在前列腺癌进展中的潜在意义促使我们使用这些POPs的低剂量挑战离体和体内模型。我们发现，二恶英或PCB-153的暴露增加了前列腺癌细胞的生长和转移标志物，在体外和移植到NOD-SCID小鼠中都是如此。暴露还在Ptenpc-/-小鼠中诱导了组织病理学上类似癌症的表现。我们发现乙酰辅酶A乙酰转酶-1（ACAT1）上调可能是一个潜在的靶点，它参与酮体代谢途径。从机制上讲，遗传抑制证实了ACAT1介导二恶英对细胞迁移的作用。通过使用公共前列腺癌数据集，我们证实了ACAT1和相关基因编码的酮体代谢途径酶（如OXCT1、BDH1和HMGCL）在晚期前列腺癌中的异常调节。为了进一步探索二恶英与ACAT1异常调节之间的联系，我们分析了来自美国老兵的一个独特前列腺肿瘤组织集合，这些老兵暴露于被称为橙剂的工业生产高度污染的二恶英。我们发现，在暴露患者中，ACAT1组织得分显著增加。我们的研究显示了二恶英和PCB-153在前列腺肿瘤中诱导促转移性程序的作用，并确定ACAT1异常调节是这一过程中的关键事件。© 2023. 作者，独家授权给施普林格自然有限公司。

Increasing evidence points towards a causal link between exposure to persistent organic pollutants (POPs) with increased incidence and aggressivity of various cancers. Among these POPs, dioxin and PCB-153 are widely found in our environment and represent a significant source of contamination. Dioxin exposure has already been linked to cancer such as non-Hodgkin's lymphoma, but remains to be more extensively investigated in other cancers. Potential implications of dioxin and PCB-153 in prostate cancer progression spurred us to challenge both ex vivo and in vivo models with low doses of these POPs. We found that dioxin or PCB-153 exposure increased hallmarks of growth and metastasis of prostate cancer cells ex vivo and in grafted NOD-SCID mice. Exposure induced histopathological carcinoma-like patterns in the Ptenpc-/- mice. We identified up-regulation of Acetyl-CoA Acetyltransferase-1 (ACAT1) involved in ketone bodies pathway as a potential target. Mechanistically, genetic inhibition confirmed that ACAT1 mediated dioxin effect on cell migration. Using public prostate cancer datasets, we confirmed the deregulation of ACAT1 and associated gene encoded ketone bodies pathway enzymes such as OXCT1, BDH1 and HMGCL in advanced prostate cancer. To further explore this link between dioxin and ACAT1 deregulation, we analyzed a unique prostate-tumour tissue collection from the USA veterans exposed to agent orange, known to be highly contaminated by dioxin because of industrial production. We found that ACAT1 histoscore is significantly increased in exposed patients. Our studies reveal the implication of dioxin and PCB-153 to induce a prometastatic programme in prostate tumours and identify ACAT1 deregulation as a key event in this process.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.