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Title: HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma

Abstract

Manipulating the posttranslational modulator of p53 is central in the regulation of its activity and function. ISGylated p53 can be degraded by the 20S proteasome. During this process, HERC5/Ceb1, an IFN-induced HECT-type E3 ligase, mediated p53 ISGylation. In this study, we indicated that HERC5 was over-expressed in both HCC tissue samples and cell lines. Knockdown of HERC5 significantly induced the expression of p53, p21 and Bax/Bcl-2 in HCC cells, resulting in apoptosis augment. Whereas, opposite results were obtained by using HERC5 over-expression. On this basis, we screened a 7, 11-disubstituted quinazoline derivative HZ-6d that could bind to the HERC5 G-rich sequence in vitro. Interestingly, HZ-6d injection effectively delayed the growth of xenografts in nude mice. In vitro, HZ-6d significantly inhibited cell growth, suppressed cell migration, induced apoptosis in HCC cells. Further studies demonstrated the anti-cancer effect of HZ-6d was associated with down-regulation of HERC5 and accumulation of p53. Collectively, we demonstrated that HZ6d is a HERC5 G-quadruplex ligand with anti-tumor properties, an action that may offer an attractive idea for restoration of p53 function in cancers. - Highlights: • HERC5 was highly expressed in HCC. • HZ-6d binds to HERC5. • HZ-6d disrupts p53 ISGylation.

Authors:
; ; ; ;  [1];  [2];  [2];  [2];  [1];  [2];  [2];  [2]
  1. School of Pharmacy, Anhui Medical University, Hefei 230032 (China)
  2. (China)
Publication Date:
OSTI Identifier:
22722952
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 334; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; BIOLOGICAL RECOVERY; HEPATOMAS; MONOCLINIC LATTICES; PHOSPHORUS 21; PLANT GROWTH; REGULATIONS

Citation Formats

Wang, Yang, Ding, Qi, Xu, Tao, Li, Chang-yao, Zhou, Dan-dan, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, Zhang, Lei, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China, and The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032. HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.09.011.
Wang, Yang, Ding, Qi, Xu, Tao, Li, Chang-yao, Zhou, Dan-dan, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, Zhang, Lei, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China, & The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032. HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma. United States. doi:10.1016/J.TAAP.2017.09.011.
Wang, Yang, Ding, Qi, Xu, Tao, Li, Chang-yao, Zhou, Dan-dan, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, Zhang, Lei, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China, and The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032. Wed . "HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma". United States. doi:10.1016/J.TAAP.2017.09.011.
@article{osti_22722952,
title = {HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma},
author = {Wang, Yang and Ding, Qi and Xu, Tao and Li, Chang-yao and Zhou, Dan-dan and Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032 and The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China and The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032 and Zhang, Lei and Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032 and The Key Laboratory of major autoimmune disease, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032,China and The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032},
abstractNote = {Manipulating the posttranslational modulator of p53 is central in the regulation of its activity and function. ISGylated p53 can be degraded by the 20S proteasome. During this process, HERC5/Ceb1, an IFN-induced HECT-type E3 ligase, mediated p53 ISGylation. In this study, we indicated that HERC5 was over-expressed in both HCC tissue samples and cell lines. Knockdown of HERC5 significantly induced the expression of p53, p21 and Bax/Bcl-2 in HCC cells, resulting in apoptosis augment. Whereas, opposite results were obtained by using HERC5 over-expression. On this basis, we screened a 7, 11-disubstituted quinazoline derivative HZ-6d that could bind to the HERC5 G-rich sequence in vitro. Interestingly, HZ-6d injection effectively delayed the growth of xenografts in nude mice. In vitro, HZ-6d significantly inhibited cell growth, suppressed cell migration, induced apoptosis in HCC cells. Further studies demonstrated the anti-cancer effect of HZ-6d was associated with down-regulation of HERC5 and accumulation of p53. Collectively, we demonstrated that HZ6d is a HERC5 G-quadruplex ligand with anti-tumor properties, an action that may offer an attractive idea for restoration of p53 function in cancers. - Highlights: • HERC5 was highly expressed in HCC. • HZ-6d binds to HERC5. • HZ-6d disrupts p53 ISGylation.},
doi = {10.1016/J.TAAP.2017.09.011},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 334,
place = {United States},
year = {2017},
month = {11}
}