LAUSR

Chromium (Cr) and its compounds have been widely used in the manufacture of many consumer products. In addition to occupational exposure of millions of industrial workers, large numbers of general population are also commonly exposed to Cr through environmental pollution resulting from continuous industrial emissions and improper waste disposal, and the presence of Cr in urban particulate matters from automobile emissions. Cr exists in several valence and the most common forms of Cr found in occupational and general environment include Cr(0), Cr(III), and Cr(VI). Only hexavalent chromium [Cr(VI)], but not Cr(0) or Cr(III), has been recognized as a human carcinogen. Many epidemiological studies have established a link between Cr(VI) exposure and increased risk of cancer and other diseases, however, the mechanism of Cr(VI) carcinogenesis has not been clearly defined. It is generally accepted that Cr(VI) works as a genotoxic carcinogen due to the fact that Cr(VI) undergoes a series of metabolic reductions inside cells to generate various reactive Cr metabolites and reactive oxygen species (ROS), producing a variety of genotoxic effects. However, much less studies have been done to investigate its non-genotoxic mechanisms. Accumulating evidence indicates that Cr(VI) exposure also causes various epigenetic changes. The goal of this study was to determine the mechanism by which Cr(VI) exposure triggers epigenetic changes and whether Cr(VI)-caused epigenetic dysregulation plays a role in chronic Cr(VI) exposure-induced cancer stem cell (CSC)-like property and cell transformation. We exposed two immortalized human bronchial epithelial cell lines (BEAS-2B and 16HBE) to 0.25 µM of K2Cr2O7 for 20 and 40 weeks to induce cell transformation, respectively. It was found that chronic Cr(VI) exposure causes epigenetic dysregulation as evidenced by the increased levels of histone H3 repressive methylation marks and the related histone-lysing methyltransferases (HMTases) in Cr(VI)-transformed cells and Cr(VI) exposure-caused human lung cancer tissues. Using pharmacological inhibitors to inactivate HMTases or shRNA knockdown of HMTases significantly decreases histone H3 repressive methylation marks and malignant phenotypes of Cr(VI)-transformed cells. Moreover, knockdown of HMTases in parental BEAS-2B cells reduces chronic Cr(VI) exposure-induced CSC-like property and cell transformation. Together, our findings indicate that chronic Cr(VI) exposure increases histone H3 repressive methylation marks by increasing the related HMTases expression; and that increased HMTases expression contributes causally to Cr(VI)-induced CSC-like property and cell transformation. Citation Format: Zhishan Wang, Jianjun Wu, Brock Humphries, Kazuya Kondo, Yiguo Jiang, Xianglin Shi, Chengfeng Yang. Histone-lysine methyltransferase up-regulation plays a causal role in hexavalent chromium-induced cancer stem cell-like property and cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4015.