Karyopherin alpha 2 (KPNA2) is a nuclear import factor that is elevated in multiple cancers. However, its molecular regulation at the transcriptional levels is poorly understood. Here we found that KPNA2 was significantly upregulated in gallbladder cancer (GBC), and the increased levels were correlated with short survival of patients. Gene knocking down of KPNA2 inhibited tumor cell proliferation and migration in vitro as well as xenografted tumor development in vivo. A typical transcription factor E2F1 associated with its DNA-binding partner DP1 bond to the promoter region of KPNA2 and induced KPNA2 expression. In contrast, an atypical transcription factor E2F7 competed against DP1 and blocked E2F1-induced KPNA2 gene activation. Mutation of the dimerization residues of E2F7 or DNA-binding domain of E2F1 abolished the suppressive effects of E2F7 on KPNA2 gene expression. In addition, KPNA2 mediated nuclear localization of E2F1 and E2F7, where they in turn controlled KPNA2 expression. Taken together, our data provided mechanistic insights into divergently transcriptional regulation of KPNA2, thus pointing to KPNA2 as a potential target for cancer therapy.

中文翻译：

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E2F1和E2F7差异调节KPNA2促进胆囊癌的发展。

Karyopherin alpha 2 (KPNA2) 是一种核输入因子，在多种癌症中升高。然而，人们对其在转录水平上的分子调控知之甚少。在这里，我们发现 KPNA2 在胆囊癌 (GBC) 中显着上调，并且增加的水平与患者的短生存期相关。KPNA2的基因敲除抑制了体外肿瘤细胞增殖和迁移以及体内异种移植肿瘤的发展。典型的转录因子 E2F1 与其 DNA 结合伴侣 DP1 结合到 KPNA2 的启动子区域并诱导 KPNA2 表达。相反，非典型转录因子 E2F7 与 DP1 竞争并阻止 E2F1 诱导的 KPNA2 基因激活。E2F7 的二聚化残基或 E2F1 的 DNA 结合结构域的突变消除了 E2F7 对 KPNA2 基因表达的抑制作用。此外，KPNA2 介导 E2F1 和 E2F7 的核定位，进而控制 KPNA2 的表达。总之，我们的数据为 KPNA2 的不同转录调控提供了机制见解，从而表明 KPNA2 是癌症治疗的潜在靶点。