Cui Yan-Hong, Wilkinson Emma, Peterson Jack, He Yu-Ying
Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
The College, Biological Science Division, University of Chicago, Chicago, IL 60637, USA.
Water (Basel). 2022 Nov 2;14(22). doi: 10.3390/w14223595. Epub 2022 Nov 8.
Inorganic arsenic is one of the well-known human skin carcinogens. However, the molecular mechanism by which arsenic promotes carcinogenesis remains unclear. Previous studies have established that epigenetic changes, including changes in DNA methylation, are among the critical mechanisms that drive carcinogenesis. -methyladenine (6mA) methylation on DNA is a widespread epigenetic modification that was initially found on bacterial and phage DNA. Only recently has 6mA been identified in mammalian genomes. However, the function of 6mA in gene expression and cancer development is not well understood. Here, we show that chronic low doses of arsenic induce malignant transformation and tumorigenesis in keratinocytes and lead to the upregulation of ALKBH4 and downregulation of 6mA on DNA. We found that reduced 6mA levels in response to low levels of arsenic were mediated by the upregulation of the 6mA DNA demethylase ALKBH4. Moreover, we found that arsenic increased ALKBH4 protein levels and that ALKBH4 deletion impaired arsenic-induced tumorigenicity and in mice. Mechanistically, we found that arsenic promoted ALKBH4 protein stability through reduced autophagy. Together, our findings reveal that the DNA 6mA demethylaseALKBH4 promotes arsenic tumorigenicity and establishes ALKBH4 as a promising target for arsenic-induced tumorigenesis.
无机砷是一种著名的人类皮肤致癌物。然而，砷促进致癌作用的分子机制仍不清楚。先前的研究已经确定，表观遗传变化，包括DNA甲基化的变化，是驱动致癌作用的关键机制之一。DNA上的N6-甲基腺嘌呤（6mA）甲基化是一种广泛存在的表观遗传修饰，最初在细菌和噬菌体DNA上发现。直到最近，6mA才在哺乳动物基因组中被鉴定出来。然而，6mA在基因表达和癌症发展中的功能尚未得到充分了解。在这里，我们表明，慢性低剂量砷可诱导角质形成细胞发生恶性转化和肿瘤发生，并导致DNA上ALKBH4的上调和6mA的下调。我们发现，低水平砷导致的6mA水平降低是由6mA DNA去甲基化酶ALKBH4的上调介导的。此外，我们发现砷增加了ALKBH4蛋白水平，并且在小鼠中敲除ALKBH4会损害砷诱导的致瘤性。从机制上讲，我们发现砷通过减少自噬促进了ALKBH4蛋白的稳定性。总之，我们的研究结果表明，DNA 6mA去甲基化酶ALKBH4促进了砷的致瘤性，并将ALKBH4确立为砷诱导肿瘤发生的一个有前景的靶点。
