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E2F1 and E2F7 differentially regulate KPNA2 to promote the development of gallbladder cancer

Oncogene volume 38, pages 1269–1281 (2019)Cite this article

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Abstract

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.

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Acknowledgements

This study was supported by Shanghai Key Laboratory of Biliary Tract Disease Research Foundation (17DZ2260200), the National Natural Science Foundation of China (No.91440203, 31620103910, 31601021, 81773043), the development fund for Shanghai talents (No. 201608), and the Precision Medicine Research Program of Shanghai Jiao Tong University School of Medicine (No.15ZH4003, DKY201507). We sincerely thank Professor Shao Rong from Shanghai Jiao Tong University School of Medicine for substantially editing the manuscript and offering constructive suggestions; and A.M. Sieuwerts from Erasmus MC, Dong Qiongzhu from Fudan University for the help.

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    1. Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China

      Shanshan Xiang, Zheng Wang, Yuanyuan Ye, Fei Zhang, Huaifeng Li, Yang Yang, Huijie Miao, Haibin Liang, Yijian Zhang, Lin Jiang, Yunping Hu & Yingbin Liu

    2. Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China

      Shanshan Xiang, Zheng Wang, Yuanyuan Ye, Fei Zhang, Huaifeng Li, Yang Yang, Huijie Miao, Haibin Liang, Yijian Zhang, Lin Jiang, Yunping Hu & Yingbin Liu

    3. Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China

      Shanshan Xiang, Zheng Wang, Yuanyuan Ye, Fei Zhang, Huaifeng Li, Yang Yang, Huijie Miao, Haibin Liang, Yijian Zhang, Lin Jiang, Yunping Hu & Yingbin Liu

    4. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

      Lei Zheng

    5. Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

      Xiyong Liu

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    Xiang, S., Wang, Z., Ye, Y. et al. E2F1 and E2F7 differentially regulate KPNA2 to promote the development of gallbladder cancer. Oncogene 38, 1269–1281 (2019). https://doi.org/10.1038/s41388-018-0494-7

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