Belužić, LucijaGrbeša, IvanaBelužić, RobertPark, Jong HoonKong, Hyun KyungKopjar, NevenkaEspadas, GuadalupeSabidó Aguadé, Eduard, 1981-Lepur, AdrianaRokić, FilipJerić, IvankaBrkljačić, LidijaVugrek, Oliver2019-12-092019-12-092018Belužić L, Grbeša I, Belužić R, Park JH, Kong HK, Kopjar N et al. Knock-down of AHCY and depletion of adenosine induces DNA damage and cell cycle arrest. Sci Rep. 2018;8(1):14012. DOI: 10.1038/s41598-018-32356-82045-2322http://hdl.handle.net/10230/43118Recently, 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.application/pdfeng© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-018-32356-8DNA damage responseHepatocellular carcinomainfo:eu-repo/semantics/openAccess