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Up-regulation of CLIC1 activates MYC signaling and forms a positive feedback regulatory loop with MYC in Hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is leading cause of tumor-related deaths worldwide. The intracellular chloride channel protein (CLIC1) plays a role in the occurrence and progression of HCC, although the underlying mechanisms are still unclear. We evaluated the CLIC1 mRNA and protein levels in both patient tissues and HCC cell lines, and analyzed the correlation between CLIC1 expression and clinical features. The biological function of CLIC1 in HCC was examined in vivo and in vitro. The upstream regulatory factors were identified by bioinformatics programs, and downstream mechanisms affecting HCC behavior have also been explored and validated. CLIC1 was up-regulated in HCC tissues and cell lines, and promoted the proliferation, invasion and migration of HCC cells in vivo and in vitro. TP53 was identified as the upstream transcription factor of CLIC1. MiR-122-5p also regulated CLIC1 levels by degrading the transcripts. More importantly, we found that the increased CLIC1 was significantly related to the activation of MYC signaling. By binding with MYC, CLIC1 enhanced the transcription activity of MYC to downstream genes, rather than by altering its expression. Finally, a positive feedback regulatory loop between CLIC1 and MYC was established. CLIC1 is closely related to the occurrence, progression and prognosis of HCC, and a promising novel therapeutic target.

SUBMITTER: Jiang X

PROVIDER: S-EPMC7471371 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Up-regulation of CLIC1 activates MYC signaling and forms a positive feedback regulatory loop with MYC in Hepatocellular carcinoma.

Jiang Xiang X Liu Yingyi Y Wang Ganggang G Yao Ye Y Mei Chengjie C Wu Xiaoling X Ma Weijie W Yuan Yufeng Y

American journal of cancer research 20200801 8

Hepatocellular carcinoma (HCC) is leading cause of tumor-related deaths worldwide. The intracellular chloride channel protein (CLIC1) plays a role in the occurrence and progression of HCC, although the underlying mechanisms are still unclear. We evaluated the CLIC1 mRNA and protein levels in both patient tissues and HCC cell lines, and analyzed the correlation between CLIC1 expression and clinical features. The biological function of CLIC1 in HCC was examined in vivo and in vitro. The upstream r ...[more]

PMID: 32905514

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Project description:BackgroundHepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.MethodsThe expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.ResultALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo.ConclusionsHBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

Dataset Information

Up-regulation of CLIC1 activates MYC signaling and forms a positive feedback regulatory loop with MYC in Hepatocellular carcinoma.

Publications

Up-regulation of CLIC1 activates MYC signaling and forms a positive feedback regulatory loop with MYC in Hepatocellular carcinoma.

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