Jo William Jaime, Ren Xuefeng, Chu Feixia, Aleshin Maria, Wintz Henri, Burlingame Alma, Smith Martyn Thomas, Vulpe Chris Dillon, Zhang Luoping
Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA.
Toxicol Appl Pharmacol. 2009 Dec 15;241(3):294-302. doi: 10.1016/j.taap.2009.08.027. Epub 2009 Sep 2.
Arsenic, a human carcinogen that is associated with an increased risk of bladder cancer, is commonly found in drinking water. An important mechanism by which arsenic is thought to be carcinogenic is through the induction of epigenetic changes that lead to aberrant gene expression. Previously, we reported that the SAS2 gene is required for optimal growth of yeast in the presence of arsenite (As(III)). Yeast Sas2p is orthologous to human MYST1, a histone 4 lysine 16 (H4K16) acetyltransferase. Here, we show that H4K16 acetylation is necessary for the resistance of yeast to As(III) through the modulation of chromatin state. We further explored the role of MYST1 and H4K16 acetylation in arsenic toxicity and carcinogenesis in human bladder epithelial cells. The expression of MYST1 was knocked down in UROtsa cells, a model of bladder epithelium that has been used to study arsenic-induced carcinogenesis. Silencing of MYST1 reduced acetylation of H4K16 and induced sensitivity to As(III) and to its more toxic metabolite monomethylarsonous acid (MMA(III)) at doses relevant to high environmental human exposures. In addition, both As(III) and MMA(III) treatments decreased global H4K16 acetylation levels in a dose- and time-dependent manner. This indicates that acetylated H4K16 is required for resistance to arsenic and that a reduction in its levels as a consequence of arsenic exposure may contribute to toxicity in UROtsa cells. Based on these findings, we propose a novel role for the MYST1 gene in human sensitivity to arsenic.
砷是一种与膀胱癌风险增加相关的人类致癌物，常见于饮用水中。砷被认为具有致癌性的一个重要机制是通过诱导表观遗传变化，导致异常的基因表达。此前，我们报道过，在亚砷酸盐（As(III)）存在的情况下，SAS2基因是酵母最佳生长所必需的。酵母Sas2p与人类MYST1同源，MYST1是一种组蛋白4赖氨酸16（H4K16）乙酰转移酶。在此，我们表明H4K16乙酰化通过调节染色质状态对酵母抗As(III)是必要的。我们进一步探讨了MYST1和H4K16乙酰化在人膀胱上皮细胞砷毒性和致癌作用中的作用。在UROtsa细胞（一种已被用于研究砷诱导致癌作用的膀胱上皮模型）中敲低MYST1的表达。MYST1的沉默降低了H4K16的乙酰化水平，并在与高环境人体暴露相关的剂量下，诱导细胞对As(III)及其毒性更强的代谢产物一甲基亚砷酸（MMA(III)）敏感。此外，As(III)和MMA(III)处理均以剂量和时间依赖性方式降低了整体H4K16乙酰化水平。这表明乙酰化的H4K16是抗砷所必需的，并且由于砷暴露导致其水平降低可能会导致UROtsa细胞中毒。基于这些发现，我们提出MYST1基因在人类对砷的敏感性方面具有新的作用。
