While hexavalent chromium [Cr(VI)] is generally considered as a genotoxic environmental carcinogen, studies showed that Cr(VI) exposure also causes epigenetic changes. However, whether Cr(VI)-caused epigenetic dysregulations plays an important role in Cr(VI) carcinogenicity remain largely unknown. The aim of this study was to determine if chronic low dose Cr(VI) exposure causes epigenetic changes, the underlying mechanism and whether chronic low dose Cr(VI) exposure-caused epigenetic dysregulation contributes causally to Cr(VI)-induced cancer stem cell (CSC)-like property and cell transformation. Two immortalized human bronchial epithelial cell lines (BEAS-2B and 16HBE) were exposed to 0.25 μM of K2Cr2O7 for 20 and 40 weeks to induce cell transformation, respectively. Cr(VI)-induced epigenetic changes were examined in Cr(VI)-transformed cells and Cr(VI) exposure-caused human lung cancer tissues. Pharmacological inhibitors and gene knockdown experiments were used to determine the role of epigenetic dysregulation in Cr(VI) carcinogenicity. We found that chronic Cr(VI) exposure causes epigenetic dysregulation as evidenced by the increased levels of histone H3 repressive methylation marks (H3K9me2 and H3K27me3) and the related histone-lysing methyltransferases (HMTases). Pharmacological inhibition or knockdown of HMTases reduces H3 repressive methylation marks and malignant phenotypes of Cr(VI)-transformed cells. Moreover, knockdown of HMTases in parental cells significantly reduces chronic Cr(VI) exposure-induced CSC-like property and cell transformation. Further mechanistic study revealed that knockdown of HMTases decreases Cr(VI) exposure-caused DNA damage. Our findings indicate that chronic Cr(VI) exposure increases H3 repressive methylation marks by increasing the related HMTases expression; and that increased expression of HMTases plays a causal role in Cr(VI)-induced CSC-like property and cell transformation.
|Number of pages||9|
|Journal||Toxicology and Applied Pharmacology|
|State||Published - Mar 1 2018|
Bibliographical noteFunding Information:
This work was supported by National Institute of Environmental Health Sciences grants 5R01ES026151-03 and 1P30ES026529-01A1 .
This research was supported by National Institutes of Health ( 5R01ES026151-03 and 1P30ES026529-01A1 ). The authors would like to thank Drs. Kathryn G. Severin and Xuefei Huang (Department of Chemistry, Michigan State University ) for their excellent technical assistance in measuring intracellular chromium levels.
This work was supported by National Institute of Environmental Health Sciences grants 5R01ES026151-03 and 1P30ES026529-01A1.
© 2018 Elsevier Inc.
- Cancer stem cell-like cell
- Cell transformation
- Hexavalent chromium
- Histone methyltransferase
ASJC Scopus subject areas