Int J Biol Sci 2022; 18(6):2553-2567. doi:10.7150/ijbs.67476 This issue

Research Paper

ENKUR expression induced by chemically synthesized cinobufotalin suppresses malignant activities of hepatocellular carcinoma by modulating β-catenin/c-Jun/MYH9/USP7/c-Myc axis

Rentao Hou1*, Yonghao Li1,2*, Xiaojun Luo1*, Wan Zhang1*, Huiling Yang3*, Yewei Zhang1, Jiahao Liu1, Shaohua Liu5, Siyuan Han6, Chen Liu1, Yun Huang7, Zhen Liu1,4✉, Aimin Li1✉, Weiyi Fang1✉

1. Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China.
2. Department of Medical Oncology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
3. School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China.
4. Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, 511436 Guangzhou, China.
5. Department of General Surgery, Pingxiang People's Hospital, Pingxiang, Jiangxi 337000, China.
6. Department of Oncology, SSL Central Hospital of Dongguan, Southern Medical University, Dongguan, Guangdong 523000, China.
7. Department of geriatric medicine, The First Affiliated Hospital of Fujian Medical University, Fujian, Fuzhou 350004, China.
*These authors contributed equally to this work.

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Citation:
Hou R, Li Y, Luo X, Zhang W, Yang H, Zhang Y, Liu J, Liu S, Han S, Liu C, Huang Y, Liu Z, Li A, Fang W. ENKUR expression induced by chemically synthesized cinobufotalin suppresses malignant activities of hepatocellular carcinoma by modulating β-catenin/c-Jun/MYH9/USP7/c-Myc axis. Int J Biol Sci 2022; 18(6):2553-2567. doi:10.7150/ijbs.67476. Available from https://www.ijbs.com/v18p2553.htm

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Abstract

Graphic abstract

ENKUR plays a crucial role in lung and colorectal cancers. Chemically synthesized cinobufotalin (CB) showed its significant anti-cancer effect in nasopharyngeal carcinoma. However, the roles of ENKUR and CB along with their correlation are still unknown in hepatocellular carcinoma (HCC). In this study, ENKUR expression in HCC tissue and cells were detected. The relationship between ENKUR expression and clinical pathology was also assessed. In vivo and in vitro experiments were conducted to explore the effects and molecular basis of ENKUR and CB in HCC. ENKUR expression was correlated with HCC progression and patient prognosis. Furthermore, ENKUR could inhibit tumor proliferation, metastasis, and sorafenib resistance in HCC. Mechanistic studies showed that ENKUR or its Enkurin domain could bind to MYH9 and decrease its expression by binding to β-catenin and inhibiting its nuclear transfer, thus decreasing c-Jun level. Low expression of MYH9 suppressed recruitment of deubiquitination enzyme USP7, promoting degradation of the c-Myc. Therefore, cell cycle and EMT signals were suppressed. CB as a safe and effective anti-cancer compound up-regulates the expression of ENKUR via inhibiting PI3K/AKT/c-Jun-mediated transcription suppression. These findings show that ENKUR induced by CB antagonizes β-catenin/c-Jun/MYH9/USP7 pathway, thus increasing c-Myc ubiquitin degradation and finally suppressing cell cycle and EMT signals.

Keywords: Chemically synthesized cinobufotalin, Hepatocellular carcinoma, Sorafenib, Malignant activities