HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 drives tumor growth and metastasis in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and lacks targeted therapies. Here, we reported a novel potential therapeutic target hematological and neurological expressed 1 like (HN1L) in HCC. First, HCC tissue microarray analysis showed that HN1L was frequently up-regulated in cancer tissues than that in normal liver tissues, which significantly associated with tumor size, local invasion, distant metastases, and poor prognosis for HCC patients. Functional studies demonstrated that ectopic expression of HN1L could increase cell growth, foci formation in monolayer culture, colony formation in soft agar and tumorigenesis in nude mice. In addition, HN1L could also promote HCC metastasis by inducing epithelial-mesenchymal transition. Inversely, silencing HN1L expression with shRNA could effectively attenuate its oncogenic function. We further showed that HN1L transcriptionally up-regulated methyltransferase like 13 (METTL13) gene in an AP-2γ dependent manner, which promoted cell proliferation and metastasis by up-regulating TCF3 and ZEB1. Importantly, administration of lentivirus-mediated shRNA interfering HN1L expression could inhibit tumorigenesis and metastasis in mice. Collectively, HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 promotes HCC growth and metastasis representing a promising therapeutic target in HCC treatment.

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Acknowledgements

This work was supported by grants from the National Basic Research Program of China (2012CB967001), the China National Key Sci-Tech Special Project of Infectious Diseases (2018ZX10723204-006-005), the National Natural Science Foundation of China (81772554, 81472250, and 81472255), the China Postdoctoral Science Fund (2018M631030), the Hong Kong Research Grant Council General Research Fund (HKU/7668/11M, 767313), the Hong Kong Theme-based Research Scheme Fund (T12-704/16-R), and the Hong Kong Research Grant Council Collaborative Research Funds (C7027-14G and C7038-14G). Professor X.-Y.G. is Sophie YM Chan Professor in Cancer Research.

Author contributions:

L.L., Y.-L.Z., C.J., and S.F.: acquisition, analysis and interpretation of data; L.L.: drafting of the manuscript; T.-T.Z., Y.-H.Z., Y.L., and D.X.: technical and material support; X.-Y.G.: study design and supervision.

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Correspondence to Xin-Yuan Guan.

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Li, L., Zheng, Y., Jiang, C. et al. HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 drives tumor growth and metastasis in hepatocellular carcinoma. Cell Death Differ 26, 2268–2283 (2019). https://doi.org/10.1038/s41418-019-0301-1

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