Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells

• Published in: Experimental cell research Vol. 340; no. 1; pp. 62 - 70
• Main Authors: Peng, Wan-xin, Xiong, Er-meng, Ge, Lu, Wan, Yan-ya, Zhang, Chun-li, Du, Feng-yi, Xu, Min, Bhat, Reyaz Ahmed, Jin, Jie, Gong, Ai-hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2016; Elsevier BV
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Autophagy; Autophagy - drug effects; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Cycle - drug effects; Cell Hypoxia - drug effects; Cellular biology; Chemo-resistance; Chemotherapy; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Egr-1; Gene Expression Regulation, Neoplastic - drug effects; HCC; Hep G2 Cells; Humans; Hypoxia; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Structure-Activity Relationship; Studies; Tumor Cells, Cultured; ANT; Egr-1; Chemo-resistance; HCC; AFP; Autophagy; CQ; DAPI, 4; 3-MA; Hypoxia; GAPDH; LC3; Ad-DN-Egr-1
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2015.12.006

Previous studies suggest that early growth response gene-1 (Egr-1) plays an important role in hypoxia-induced drug-resistance. However, the mechanism still remains to be clarified. Herein, we investigated the role of Egr-1 in hypoxia-induced autophagy and its resulted hypoxia-driven chemo-resistance in Hepatocellular Carcinoma (HCC) cells. Our data demonstrated that Egr-1 was overexpressed in HCC tissues and cells and conferred them drug resistance under hypoxia. Mechanistically, Egr-1 transcriptionally regulated hypoxia-induced autophagy by binding to LC3 promoter in HCC cells, which resulted in resistance of HCC cells to chemotherapeutic agents; while dominant negative Egr-1 could inhibit autophagy level, and thus enhanced the sensitivity of HCC cells to chemotherapeutic agents, indicating that hypoxia-induced Egr-1 expression enhanced drug resistance of HCC cells likely through autophagy. Accordingly, it is suggested that a mechanism of hypoxia/Egr-1/autophagy axis might be involved in drug resistance in HCC. •Hypoxia-induced autophagy is regulated by Egr-1.•Egr-1 regulates chemoresistance by directly regulating LC3 under hypoxia.•The hypoxia/Egr-1/autophagy axis represents a novel target for HCC therapy.