Aldo-keto reductase family 1 member C1 (AKR1C1) promotes malignancy of Non-Small Cell Lung Cancer (NSCLC) by activating Signal Transducer and Activator of Transcription 3 (STAT3) pathway. However, how the pro-metastatic functions of AKR1C1 are switched on/off remains unknown.

Methods: Immunoprecipitation and LC-MS/MS analyses were performed to identify the acetylation on AKR1C1 protein, and the functional analyses (in vitro and in vivo) were performed to depict the contribution of acetylation to the pro-metastatic effects of AKR1C1.

Results: Here we report that acetylated AKR1C1 on two lysine residues K185 & K201 is critical to its pro-metastatic role. The acetylation modification has no impact on the canonical enzymatic activity of AKR1C1, while it is required for the interaction between AKR1C1 to STAT3, which triggers the downstream transduction events, ultimately mobilizing cells. Importantly, the deacetylase Sirtuin 2 (SIRT2) is capable of deacetylating AKR1C1, inhibiting the transactivation of STAT3 target genes, thus suppressing the migration of cells.

Conclusion: Acetylation on Lysines 185 and 201 of AKR1C1 dictates its pro-metastatic potential both in vitro and in vivo, and the reverting of acetylation by Sirtuin 2 provides potential therapeutic targets for treatment against metastatic NSCLC patients with high AKR1C1 expression.

Aldo-酮基还原酶家族1成员C1（AKR1C1）通过激活信号转导子和转录激活子3（STAT3）途径促进非小细胞肺癌（NSCLC）的恶性。但是，如何打开/关闭AKR1C1的前转移功能仍然未知。

方法：进行免疫沉淀和LC-MS / MS分析以鉴定AKR1C1蛋白的乙酰化作用，并进行功能分析（体内和体外）以描述乙酰化作用对AKR1C1促转移作用的影响。

结果：在这里我们报道在两个赖氨酸残基K185和K201上乙酰化的AKR1C1对其促转移作用至关重要。乙酰化修饰对AKR1C1的规范酶活性没有影响，而AKR1C1与STAT3之间的相互作用则需要这种作用，从而触发下游的转导事件，最终动员细胞。重要的是，脱乙酰基酶Sirtuin 2（SIRT2）能够使AKR1C1脱乙酰基，从而抑制STAT3目标基因的反式激活，从而抑制细胞的迁移。

结论：AKR1C1赖氨酸185和201的乙酰化决定了其在体内和体外的转移前潜力，而Sirtuin 2乙酰化的逆转提供了潜在的治疗靶点，用于治疗高AKR1C1表达的转移性NSCLC患者。