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HIPK2 suppresses tumor growth and progression of hepatocellular carcinoma through promoting the degradation of HIF-1α

Oncogene volume 39, pages 2863–2876 (2020)Cite this article

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Abstract

Aberrant angiogenesis of hepatocellular carcinoma (HCC) leads to tumor growth and local or distant metastasis. Uncovering the underlying mechanisms for the neoangiogenesis of HCC can provide novel potential therapeutic targets in the clinic. Here, we reported that serine/threonine homeodomain-interacting protein kinase 2 (HIPK2) was frequently downregulated in HCC tissues compared with the adjacent normal tissues, and patients with lower HIPK2 protein expression were associated with worse overall survival. Both in vitro and in vivo, HIPK2 inhibited the migration of HCC cells, as well as tumor growth and metastasis in xenograft and orthotopic syngeneic HCC mouse models. Furthermore, HIPK2 inhibited the angiogenesis in HCC tumors. Under the hypoxic condition, HIPK2 knockdown enhanced the angiogenesis and the key regulator, HIF-1α signaling pathway; however, HIPK2 overexpression downregulated the tumoral angiogenesis and HIF-1α signaling. In HCC cells, HIPK2 could directly bind to HIF-1α and stimulate the ubiquitination of HIF-1α for proteasomal degradation. HIF-1α knockout partially rescued the promoting effect of HIPK2 depletion on angiogenesis and tumor growth. In conclusion, the downregulation of HIPK2 could enhance the angiogenesis in HCC through inducing the HIF-1α pathway, and further contribute to tumor growth and metastasis, which may provide a novel therapeutic strategy for HCC.

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Fig. 1: HIPK2 is downregulated in HCC tissues compared with normal tissues and is associated with the overall survival of HCC patients.
Fig. 2: HIPK2 inhibits the tumor growth and distant metastasis of HCC in vivo.
Fig. 3: HIPK2 inhibits the metastasis of HCC cells in vitro and in vivo.
Fig. 4: HIPK2 inhibits the angiogenesis of the HCC cells under the hypoxia condition.
Fig. 5: HIPK2 stimulated HIF-1α degradation through the ubiquitin-proteasome pathway.
Fig. 6: HIF-1α signaling pathway underlies the tumor suppressor actives of HIPK2 in HCC.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2018YFC2000700, 2018ZX10302205, and 2017YFC0907001), the National Natural Science Foundation of China (81630086, 81573161, 81973078, and 81427805), the Science and Technology Commission of Shanghai Municipality (16391903700), the Shanghai Municipality Health Commission (20164Y0250 and 2017YQ0059), the Major Science and Technology Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-01-E00059), the Key Research Program (ZDRW-ZS-2017-1) of the Chinese Academy of Sciences, Shanghai Municipal Human Resources and Social Security Bureau (2018060), Science and Technology Commission of Jiading Distinct (JDKW-2017-W09), and Shanghai Jiao Tong University (YG2017MS85).

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  1. These authors contributed equally: Peizhan Chen, Xiaohua Duan

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  1. State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, PR China

    Peizhan Chen, Xiaoguang Li, Jingquan Li, Qian Ba & Hui Wang

  2. CAS Key Laboratory of Nutrition, Metabolism and Food safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, PR China

    Peizhan Chen, Xiaohua Duan & Hui Wang

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Chen, P., Duan, X., Li, X. et al. HIPK2 suppresses tumor growth and progression of hepatocellular carcinoma through promoting the degradation of HIF-1α. Oncogene 39, 2863–2876 (2020). https://doi.org/10.1038/s41388-020-1190-y

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