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      Egr-1 regulates irradiation-induced autophagy through Atg4B to promote radioresistance in hepatocellular carcinoma cells

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          Abstract

          Although hepatocellular carcinoma (HCC) is usually response to radiation therapy, radioresistance is still the major obstacle that limits the efficacy of radiotherapy for HCC patients. Therefore, further investigation of underlying mechanisms in radioresistant HCC cells is warranted. In this study, we determined the effect of early growth response factor (Egr-1) on irradiation-induced autophagy and radioresistance in HCC cell lines SMMC-7721 and HepG2. We showed that autophagy-related gene 4B (Atg4B) is induced by Egr-1 upon ionizing radiation (IR) in HCC cells. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) revealed that Egr-1 binds to the Atg4B promoter to upregulate its expression in HCC cells. Suppression of Egr-1 function by dominant-negative Egr-1 dampens IR-induced autophagy, cell migration, and increases cell sensitivity to radiotherapy. Together, these results suggest that Egr-1 contributes to HCC radioresistance through directly upregulating target gene Atg4B, which may serve as a protective mechanism by preferential activation of the autophagy.

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          A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles.

          S Paglin, T Hollister, T Delohery … (2001)
          The mechanisms underlying neoplastic epithelial cell killing by ionizing radiation are largely unknown. We discovered a novel response to radiation manifested by autophagy and the development of acidic vesicular organelles (AVO). Acidification of AVO was mediated by the vacuolar H+-ATPase. Staining with the lysosomotropic agent acridine orange enabled us to quantify AVO accumulation and to demonstrate their time- and dose-dependent appearance. The appearance of AVO occurred in the presence of the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethyl ketone, but was inhibited by 3-methyladenine, an inhibitor of autophagy. The accretion of AVO in surviving progenies of irradiated cells, and the increased incidence of clonogenic death after inhibition of vacuolar H+-ATPase suggest that formation of acidic organelles represents a novel defense mechanism against radiation damage.
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            Egr-1 Regulates Autophagy in Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

            Zhi-Hua Chen, Hong Kim, Frank Sciurba … (2008)
            Background Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear. Methodology and Principal Findings Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1 −/− mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema. Conclusions We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
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              The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells.

              Stephanie L Lomonaco, Susan Finniss, Cunli Xiang … (2009)
              Malignant gliomas are characterized by a short median survival which is largely impacted by the resistance of these tumors tochemo- and radiotherapy. Recent studies suggest that a small subpopulation of cancer stem cells, which are highly resistant to gamma-radiation, has the capacity to repopulate the tumors and contribute to their malignant progression. gamma-radiation activates the process of autophagy and inhibition of this process increases the radiosensitivity of glioma cells; however, the role of autophagy in the resistance of glioma stem cells (GSCs) to radiation has not been yet reported. In this study we examined the induction of autophagy by gamma-radiation in CD133+ GSCs. Irradiation of CD133+ cells induced autophagy within 24-48 hr and slightly decreased the viability of the cells. gamma-radiation induced a larger degree of autophagy in the CD133+ cells as compared with CD133- cells and the CD133+ cells expressed higher levels of the autophagy-related proteins LC3, ATG5 and ATG12. The autophagy inhibitor bafilomycin A1 and silencing of ATG5 and beclin1 sensitized the CD133+ cells to gamma-radiation and significantly decreased the viability of the irradiated cells and their ability to form neurospheres. Collectively, these results indicate that the induction of autophagy contributes to the radioresistance of these cells and autophagy inhibitors may be employed to increase the sensitivity of CD133+ GSCs to gamma-radiation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncogenesis
                Journal ID (iso-abbrev): Oncogenesis
                Title: Oncogenesis
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2157-9024
                Publication date (Print): January 2017
                Publication date (Electronic): 30 January 2017
                Publication date PMC-release: 1 January 2017
                Volume: 6
                Issue: 1
                Page: e292
                Affiliations
                [1 ]Department of Oncology, the Affiliated People's Hospital of Jiangsu University , Zhenjiang, Jiangsu, China
                [2 ]Department of Cell biology, School of Medicine, Jiangsu University , Zhenjiang, China
                [3 ]Department of Gastroenterology, Affiliated Hospital of Jiangsu University , Zhenjiang, Jiangsu, China
                Author notes
                [* ]Department of Oncology, the Affiliated People's Hospital of Jiangsu University , Zhenjiang, Jiangsu 212002, China. E-mail: wuchaoyang9@ 123456163.com
                [4]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: oncsis201691
                DOI: 10.1038/oncsis.2016.91
                PMC ID: 5294254
                PubMed ID: 28134935
                SO-VID: 1256cc95-6591-4c68-a1e2-df139e302032
                Copyright © Copyright © 2017 The Author(s)
                License:

                Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 12 September 2016
                Date revision received : 01 December 2016
                Date accepted : 20 December 2016
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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