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

Lei Li,Yin-Li Zheng,Xin-Yuan Guan,Yan Li,Chen Jiang,Ying-Hui Zhu,Ting-Ting Zeng,Shuo Fang,Dan Xie

doi:10.1038/s41418-019-0301-1

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 representinga promising therapeutic target in HCC treatment.

Highlights

The human hematopoietic-expressed and neurologicexpressed sequence 1-like (HN1L), known as jupiter microtubule associated homolog 2, C16orf34 or L11, wasThese authors contributed : Lei Li, Yin-Li Zheng, Chen Jiang, Shuo FangEdited by J.P
As HN1L is a crucial instigator in regulating Hepatocellular carcinoma (HCC) cell growth and metastasis, we investigate the potential of targeting HN1L by the lentivirus containing the shRNA targeting HN1L (LV-shHN1L) for suppressing HCC progression
Ectopic expression of HN1L could increase cell growth rate, frequencies of foci formation and tumor spheres in soft agar, and tumorigenesis in nude mice

Summary

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The human hematopoietic-expressed and neurologicexpressed sequence 1-like (HN1L), known as jupiter microtubule associated homolog 2, C16orf or L11, was. Hematopoietic-expressed and neurologic-expressed sequence 1 (HN1), a homologous gene of HN1L, is located on chromosome 17q25.2 and encodes a 16.5 kDa protein. HN1 contributes to prostate cell migration through controlling the stability of β-catenin interaction with E-cadherin in adherent junctions [9] These evidences suggest that HN1 is critical for regulating cancer cell growth and metastasis. Mechanism studies revealed that HN1L transcriptionally increase methyltransferase like 13 (METTL13) expression by promoting the transcriptional activity of AP-2γ via a direct protein-protein interaction. Up-regulated METTL13 promotes tumor growth and metastasis by increasing the expression of TCF3 and ZEB1. These data suggest that the transcriptional axis HN1L/AP-2γ/METTL13/TCF3-ZEB1 is a novel pathway contributing to the aggressiveness and poor prognosis of HCC

Results

Discussion

Methods