Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.

脂肪酸合酶 (FASN) 通常在前列腺癌中过表达并与肿瘤进展有关。FASN 负责脂肪酸棕榈酸酯的从头合成；蛋白质棕榈酰化的基石。最近的研究表明，FASN 除了在促进细胞增殖方面的既定作用外，还可能促进侵袭。我们现在发现 FASN 表达的消耗会增加前列腺癌细胞的粘附性，削弱 HGF 介导的细胞迁移并减少 3D 侵袭。这些运动性变化表明 FASN 可以介导肌动蛋白细胞骨架重塑。一个已知是 Rho 家族 GTP 酶下游的过程。在这里，我们证明了 FASN 表达的调节特别影响非典型 GTPase RhoU 的棕榈酰化。FASN 耗竭细胞中 RhoU 活性受损导致桩蛋白丝氨酸磷酸化下游的粘附周转减少，这可通过添加外源性棕榈酸酯来挽救。此外，典型的 Cdc42 表达依赖于 RhoU 的棕榈酰化状态。因此，我们发现了直接影响细胞迁移潜力的 FASN、RhoU 和 Cdc42 之间的新关系。这些结果提供了令人信服的证据，表明 FASN 活性直接促进细胞迁移并支持 FASN 作为转移性前列腺癌的潜在治疗靶点。直接影响细胞迁移潜力的 RhoU 和 Cdc42。这些结果提供了令人信服的证据，表明 FASN 活性直接促进细胞迁移并支持 FASN 作为转移性前列腺癌的潜在治疗靶点。直接影响细胞迁移潜力的 RhoU 和 Cdc42。这些结果提供了令人信服的证据，表明 FASN 活性直接促进细胞迁移并支持 FASN 作为转移性前列腺癌的潜在治疗靶点。