0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop

• Published in: Scientific reports Vol. 7; no. 1; pp. 4396 - 9
• Main Authors: Xia, Caixia, Shui, Liyan, Lou, Guohua, Ye, Bingjue, Zhu, Wei, Wang, Jing, Wu, Shanshan, Xu, Xiao, Mao, Long, Xu, Wanhong, Chen, Zhi, Liu, Yanning, Zheng, Min
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/51; 13/89; 631/154/1435; 631/67/1059/153; Acylation; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Chemotherapy; Computational Biology - methods; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA damage; DNA Damage - drug effects; Feedback; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; MicroRNAs - genetics; miRNA; multidisciplinary; p53 Protein; Proteins; Rodents; Science; Science (multidisciplinary); Signal transduction; SIRT1 protein; Sirtuin 1 - genetics; Transcriptome; Transfection; Tumor Suppressor Protein p53 - genetics; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-04487-x

DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular response profiling (TCRP) based on unique DNA-damage characteristics. We used human HCC cell lines and HCC xenograft mouse model to analyze the anti-cancer effects of 0404. Transcriptome and miRNA arrays were used to verify the anti-cancer mechanism of 0404. It was confirmed that p53 signaling pathway was crucial in 0404 anti-cancer activity and the expression of miR-34a, a key tumor-suppressive miRNA, was up-regulated in 0404-treated HepG2 cells. MiR-34a expression was also down-regulated in HCCs compared with corresponding non-cancerous hepatic tissues. We further identified the mechanisms of 0404 in HepG2 cells. 0404 increased miR-34a expression and acylation p53 protein levels and decreased SIRT1 protein levels in a concentration-dependent manner. The sensitivity of HepG2 cells to 0404 was significantly decreased by transfection with miR-34a inhibitors and SIRT1 protein levels were up-regulated by miR-34a inhibition. Our findings show that 0404 is probably an attractive agent for treating HCC, especially in HCC with wide type (WT) p53, through forming a p53/miR-34a/SIRT1 signal feedback loop to promote cell apoptosis.