Ruđer Bošković Institute, Laboratory for Advanced Genomics, 10000, Zagreb, Croatia.
Bar-Ilan University, Cellular and Developmental Biology, Ramat-Gan, 5290002, Israel.
Sci Rep. 2018 Sep 18;8(1):14012. doi: 10.1038/s41598-018-32356-8.
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.
最近，有报道称 S-腺苷同型半胱氨酸水解酶 (AHCY) 的活性与癌症之间存在功能联系。由于 AHCY 的特性包括 S-腺苷同型半胱氨酸的水解和维持细胞甲基化潜能，因此 AHCY 与癌症之间的联系并不明显。AHCY 影响细胞周期或细胞增殖的机制尚未得到证实。为了阐明 AHCY 驱动的癌症特异性机制，我们采用了多组学方法来研究 AHCY 敲低对肝癌细胞的影响。在这里，我们表明，降低 AHCY 活性会导致腺苷耗竭，激活 DNA 损伤反应 (DDR)，导致细胞周期停滞、增殖率下降和 DNA 损伤。这些效应背后的潜在机制可能适用于那些具有显著内源性 AHCY 水平和/或依赖其微环境中高浓度腺苷的癌症类型。因此，腺苷监测可能被用作预防肝病的措施，而诱导的腺苷耗竭可能是在诊断出的癌症中引发 DDR 的理想方法，从而为靶向治疗开辟新途径。此外，将 AHCY 纳入突变筛选作为潜在风险因素可能是一种有益的预防措施。
