SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway

Autor: Steven A. Weinman, Jordan Voss, Jie Zhao, Josiah Cox, Abby Adams, Anusha Vittal, Brian Bridges, Ann L. Wozniak, Zhuan Li
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
Mice
0302 clinical medicine
TACE resistance
Sirtuins
HCC
Gene knockdown
Cell Death
Liver Neoplasms
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunohistochemistry
3. Good health
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Female
Liver cancer
medicine.drug
Protein Binding
Signal Transduction
Programmed cell death
Carcinoma
Hepatocellular
Deacetylation
NOXA
lcsh:RC254-282
03 medical and health sciences
Cell Line
Tumor
medicine
Carcinoma
Animals
Humans
Doxorubicin
Histone deacetylase
neoplasms
Aged
Cell Proliferation
Neoplasm Staging
business.industry
Research
medicine.disease
digestive system diseases
Disease Models
Animal
030104 developmental biology
Apoptosis
Drug Resistance
Neoplasm
Cancer research
Neoplasm Grading
Tumor Suppressor Protein p53
business
Zdroj: Journal of Experimental & Clinical Cancer Research : CR
Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-16 (2019)
ISSN: 1756-9966
0392-9078
Popis: Background Optimal therapeutic strategies for hepatocellular carcinoma (HCC) patients are still challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Growing evidence shows that genetic and epigenetic alterations are involved in HCC progression and resistance to therapy, however the molecular mechanisms underlying resistance to therapy have not been fully understood. Methods Expression of SIRT7 in 17 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry and Western blot. The mRNA expression of SIRT7 in 20 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by quantitative RT-PCR. The biologic consequences of overexpression and knockdown of SIRT7 in HCC therapy sensitivity were studied in vitro and in vivo. Interaction between SIRT7 and p53 were studied in HCC cell lines. Results SIRT7 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with TACE-resistance and poor survival (P = 0.008.) Depletion of SIRT7 from multiple liver cancer cell lines significantly increased doxorubicin toxicity while overexpression of SIRT7 largely abolished doxorubicin induced apoptosis. At the molecular level, we observed that SIRT7 interacts with and induces deacetylation of p53 at lysines 320 and 373. Deacetylated p53 showed significantly less affinity for the NOXA promoter and its transcription. In mouse xenografts, SIRT7 suppression increased doxorubicin induced p53 activation, inhibited tumor growth and induced apoptosis. Conclusion The newly identified SIRT7-p53-NOXA axis partially illustrates the molecular mechanism of HCC resistance to therapy and represents a novel potential therapeutic target for HCC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1246-4) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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