Epigenetic and epitranscriptomic mechanisms of chromium carcinogenesis

Abstract

Hexavalent chromium [Cr(VI)], a Group I carcinogen classified by the International Agency for Research on Cancer (IARC), represents one of the most common occupational and environmental pollutants. The findings from human epidemiological and laboratory animal studies show that long-term exposure to Cr(VI) causes lung cancer and other cancer. Although Cr(VI) is a well-recognized carcinogen, the mechanism of Cr(VI) carcinogenesis has not been well understood. Due to the fact that Cr(VI) undergoes a series of metabolic reductions once entering cells to generate reactive Cr metabolites and reactive oxygen species (ROS) causing genotoxicity, Cr(VI) is generally considered as a genotoxic carcinogen. However, more and more studies have demonstrated that acute or chronic Cr(VI) exposure also causes epigenetic dysregulations including changing DNA methylation, histone posttranslational modifications and regulatory non-coding RNA (microRNA and long non-coding RNA) expressions. Moreover, emerging evidence shows that Cr(VI) exposure is also capable of altering cellular epitranscriptome. Given the increasingly recognized importance of epigenetic and epitranscriptomic dysregulations in cancer initiation and progression, it is believed that Cr(VI) exposure-caused epigenetic and epitranscriptomic changes could play important roles in Cr(VI) carcinogenesis. The goal of this chapter is to review the epigenetic and epitranscriptomic effects of Cr(VI) exposure and discuss their roles in Cr(VI) carcinogenesis. Better understanding the mechanism of Cr(VI) carcinogenesis may identify new molecular targets for more efficient prevention and treatment of cancer resulting from Cr(VI) exposure.

Keywords: DNA methylation; Epigenetics; Epitranscriptome; Hexavalent chromium; Histone posttranslational modification; Long non-coding RNA; N(6)-methyladenosine (m(6)A); Non-coding RNA; RNA modification; microRNA.