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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma
1School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China; 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, China.
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.
Insights
HERC5 E3 ligase promotes hepatocellular carcinoma (HCC) progression by degrading p53. A novel quinazoline derivative, HZ-6d, targets HERC5, inhibiting HCC growth and restoring p53 function.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Posttranslational modification of p53 is crucial for its function.
- HERC5 (HECT-type E3 ubiquitin ligase) mediates p53 ISGylation and subsequent proteasomal degradation.
- HERC5 is overexpressed in hepatocellular carcinoma (HCC).
Purpose of the Study:
- To investigate the role of HERC5 in HCC progression.
- To identify and characterize a novel therapeutic agent targeting HERC5 for HCC treatment.
Main Methods:
- Analysis of HERC5 expression in HCC tissues and cell lines.
- Knockdown and overexpression of HERC5 in HCC cells.
- In vitro screening for HERC5 G-rich sequence binders.
- In vitro and in vivo assays to evaluate the anti-cancer effects of HZ-6d.
- Western blot analysis to assess protein levels (p53, p21, Bax/Bcl-2).
Main Results:
- HERC5 knockdown increased p53, p21, and Bax/Bcl-2 expression, inducing apoptosis in HCC cells.
- HERC5 overexpression yielded opposite results.
- HZ-6d, a quinazoline derivative, binds to the HERC5 G-rich sequence.
- HZ-6d inhibited HCC cell growth, migration, and induced apoptosis in vitro.
- HZ-6d delayed xenograft growth in nude mice.
- HZ-6d's anti-cancer effects were linked to HERC5 downregulation and p53 accumulation.
Conclusions:
- HERC5 plays a pro-tumorigenic role in HCC by promoting p53 degradation.
- HZ-6d is a HERC5 G-quadruplex ligand with significant anti-tumor properties.
- HZ-6d represents a potential therapeutic strategy for restoring p53 function in HCC.
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