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Knock-down of AHCY and depletion of adenosine induces DNA damage and cell cycle arrest

Belužić, Lucija; Grbeša, Ivana; Belužić, Robert; Park, Jong Hoon; Kong, Hyun Kyung; Kopjar, Nevenka; Espadas, Guadalupe; Sabidó, Eduard; Lepur, Adriana; Rokić, Filip; Jerić, Ivanka; Brkljačić, Lidija; Vugrek, Oliver (2018) Knock-down of AHCY and depletion of adenosine induces DNA damage and cell cycle arrest. Scientific Reports, 8 . ISSN 2045-2322

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Abstract

Recently, functional connections between S-adenosylhomocysteine hydrolase (AHCY) activity and cancer have been reported. As the properties of AHCY include the hydrolysis of S- adenosylhomocysteine and maintenance of the cellular methylation potential, the connection between AHCY and cancer is not obvious. The mechanisms by which AHCY influences the cell cycle or cell proliferation have not yet been confirmed. To elucidate AHCY- driven cancer-specific mechanisms, we pursued a multi-omics approach to investigate the effect of AHCY-knockdown on hepatocellular carcinoma cells. Here, we show that reduced AHCY activity causes adenosine depletion with activation of the DNA damage response (DDR), leading to cell cycle arrest, a decreased proliferation rate and DNA damage. The underlying mechanism behind these effects might be applicable to cancer types that have either significant levels of endogenous AHCY and/or are dependent on high concentrations of adenosine in their microenvironments. Thus, adenosine monitoring might be used as a preventive measure in liver disease, whereas induced adenosine depletion might be the desired approach for provoking the DDR in diagnosed cancer, thus opening new avenues for targeted therapy. Additionally, including AHCY in mutational screens as a potential risk factor may be a beneficial preventive measure.

Item Type: Article
Uncontrolled Keywords: DNA damage ; liver cancer ; RNAseq ; SILAC ; methylation potential ; SAM/SAH ratio
Subjects: NATURAL SCIENCES > Biology
Divisions: Division of Molecular Medicine
Projects:
Project titleProject leaderProject codeProject type
Enhancement of the Innovation Potential in SEE through new Molecular Solutions in Research and Development-INNOMOLUNSPECIFIED316289EK
Depositing User: Sofija Konjević
Date Deposited: 03 Jan 2019 13:52
Last Modified: 03 Jan 2019 13:52
URI: http://fulir.irb.hr/id/eprint/4389
DOI: 10.1038/s41598-018-32356-8

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