肝细胞癌（HCC）是全球癌症死亡的主要原因之一。发病率逐渐增高，导致对新的治疗选择的需求无法满足。近期，虽然在体外矛盾的研究结果显示sirtuin-2（Sirt2）可能作为HCC的潜在治疗方法，但sirtuin-2的抑制在HCC中的角色既可能是肿瘤促进因子，也可能是肿瘤抑制因子。Sirt2作为一种赖氨酸脱乙酰酶酶活的功能已得到一定的了解，然而对其生物学影响的了解还很有限，尽管其有关几种老年相关疾病的暗示。本研究采用诱导c-MYC基因转基因在Sirt2+/+和Sirt2-/-小鼠中的方法，评估了Sirt2在HCC中的作用。结果表明，Sirt2-/- HCC 小鼠的肝肿瘤较小、增殖较低、分化较好，暗示其在该背景下具有肿瘤促进作用。此外，Sirt2-/- HCC中的c-MYC致癌蛋白明显减少，并且c-MYC核定位减少。RNA-seq显示，由于Sirt2的损失，只有三个基因明显发生失调，暗示了Sirt2介导的乙酰化组学改变是潜在机制，并且抑制Sirt2将不会干扰致癌转录组。本研究的发现表明，Sirt2抑制有望成为减缓HCC生长的有希望的分子靶点。

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths globally. Incidence rates are steadily increasing, creating an unmet need for new therapeutic options. Recently, the inhibition of sirtuin-2 (Sirt2) was proposed as a potential treatment for HCC, despite contradictory findings of its role as both a tumor promoter and suppressor in vitro. Sirt2 functions as a lysine deacetylase enzyme. However, little is known about its biological influence, despite its implication in several age-related diseases. This study evaluated Sirt2's role in HCC in vivo using an inducible c-MYC transgene in Sirt2+/+ and Sirt2-/- mice. Sirt2-/- HCC mice had smaller, less proliferative, and more differentiated liver tumors, suggesting that Sirt2 functions as a tumor promoter in this context. Furthermore, Sirt2-/- HCCs had significantly less c-MYC oncoprotein and reduction in c-MYC nuclear localization. The RNA-seq showed that only three genes were significantly dysregulated due to loss of Sirt2, suggesting the underlying mechanism is due to Sirt2-mediated changes in the acetylome, and that the therapeutic inhibition of Sirt2 would not perturb the oncogenic transcriptome. The findings of this study suggest that Sirt2 inhibition could be a promising molecular target for slowing HCC growth.