Abstract A26: Mechanism of hexavalent chromium carcinogenesis—the role of epigenetic deregulation-caused oncogene activation
Authors: Yang Chengfeng , Lin Martina , Yang Ping , Li Yunfei , Maddy Drew , Wang Zhishan 
Published: June 2022

Hexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants. Although Cr(VI) is a well-recognized carcinogen causing lung cancer in humans, the mechanism of Cr(VI) carcinogenesis has not been clearly defined. While Cr(VI) is generally considered a genotoxic carcinogen, studies showed that Cr(VI) exposure also causes nongenotoxic effects such as epigenetic changes in Cr(VI)-exposed cells and Cr(VI) exposure-caused human lung cancer tissues. However, how epigenetics deregulation promotes Cr(VI) carcinogenesis remains largely unknown. In this study, we found that chronic Cr(VI) exposure caused epigenetic deregulations as evidenced by the increased levels of histone H3 repressive methylation marks (H3K9me2 and H3K27me3) and the related histone-lysing methyltransferases (HMTases) in Cr(VI)-transformed cells and Cr(VI) exposure-caused human lung cancer tissues. Using pharmacologic inhibitors to inactivate HMTases or shRNA knockdown of HMTases significantly decreased histone H3 repressive methylation marks and malignant phenotypes of Cr(VI)-transformed cells. Moreover, knockdown of HMTases in immortalized human bronchial epithelial cells significantly reduced chronic low dose of Cr(VI) exposure-induced cancer stem cell (CSC)-like property and cell transformation. Mechanistic studies revealed that increased HMTase expression by chronic Cr(VI) exposure caused downregulation of the expression of microRNA-494 (miR-494). Furthermore, stably overexpressing miR-494 in immortalized human bronchial epithelial cells significantly reduced chronic Cr(VI) exposure-induced CSC-like property, cell malignant transformation, and tumorigenesis. By bioinformatics analysis and literature searching we found that the proto oncogene c-Myc is a target of miR-494. Western blot analysis revealed that c-Myc expression level is significantly increased in Cr(VI)-transformed cells. To determine the role of c-Myc in Cr(VI)-induced cell transformation, we stably knocked down c-Myc expression in Cr(VI)-transformed human bronchial epithelial cells and found that c-Myc knockdown significantly reduced Cr(VI)-induced CSC-like property and tumorigenesis. Moreover, we also stably overexpressed c-Myc in Cr(VI)-exposed miR-494 overexpressing cells and found that c-Myc overexpression significantly overcame the inhibitory effect of miR-494 on Cr(VI)-induced CSC-like property and tumorigenesis. Together, these findings suggest that Cr(VI)-caused epigenetic deregulation contributes significantly and causally to Cr(VI) induced CSC-like property and tumorigenesis by downregulating miR-494, leading to increased expression of the proto oncogene c-Myc.

Citation Format: Chengfeng Yang, Martina Lin, Ping Yang, Yunfei Li, Drew Maddy, Zhishan Wang. Mechanism of hexavalent chromium carcinogenesis—the role of epigenetic deregulation-caused oncogene activation [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A26.