Hexavalent chromium [Cr(VI)] is one of the most common environmental pollutants causing lung and other cancer. The mechanism of Cr(VI) carcinogenesis has not been elucidated. The long-term goal of this study is to determine the mechanism of Cr(VI) carcinogenicity and identify targets for better treatment and prevention of lung cancer resulting from Cr(VI) exposure. Epigenetics refers to heritable changes in the pattern of gene expression that are not caused by changes in DNA sequence, but are mediated by DNA methylation, histone posttranslational modifications, microRNAs and long noncoding RNAs. Cancer stem cells (CSCs) are cancer cells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiating cells. Genomic imprinting refers to an epigenetic mechanism by which certain genes are expressed in a parent- of-origin-specific manner, restricting their expression from only one of the two parental chromosomes. Many studies demonstrated that deregulation of epigenetics and genomic imprinting plays key roles in carcinogenesis. Accumulating evidence shows that Cr(VI) also causes epigenetic effects such as changing DNA methylation and histone posttranslational modifications. However, the mechanisms by which Cr(VI) triggers these epigenetic modifications remain largely unknown and whether these epigenetic modifications play a causal role in Cr(VI) carcinogenesis are not clear. Our preliminary studies found: (i) Chronic Cr(VI) exposure induces CSC-like property and cell malignant transformation; (ii) Chronic Cr(VI) exposure increases the levels of several HMTases, which play a causal role in Cr(VI)-induced CSC-like property and cell transformation; (iii) Higher levels of H3 repressive methylation marks and their related HMTases are also detected in lung cancer tissues of humans exposed to chromium; (iv) Up-regulation of HMTases plays a crucial role in chronic Cr(VI) exposure-caused deregulation of Dlk1-Dio3 genomic imprinting cluster; (v) miR-494 down-regulation plays a causal role in Cr(VI)- induced cell transformation; and (vi) Oxidative stress increases the levels of HMTases. Based on literature and our preliminary data, we hypothesize: (i) Cr(VI) exposure generates oxidative stress, which increases the levels of HMTases; (ii) Up-regulation of HMTases deregulates the Dlk1-Dio3 genomic imprinting cluster, which decreases the level of miR-494; and (iii) Down-regulation of miR-494 increases the levels of its targets and key CSC factors c-Myc and BMI1, which produce CSC-like property promoting Cr(VI)-induced cell transformation and tumorigenesis. This proposed study not only fills the knowledge gap of epigenetics and Cr(VI) carcinogenesis, but also provides novel mechanistic insights for the crucial role of oxidative stress in Cr(VI) carcinogenesis.
Three aims are proposed:
Aim 1 : Induction of CSC-like property by down-regulating miR-494 of Dlk1-Dio3 imprinting cluster and its role in Cr(VI)-induced cell transformation and tumorigenesis.
Aim 2 : Down-regulation of miR-494 by chronic Cr(VI) exposure-induced HMTases through deregulating Dlk1-Dio3 genomic imprinting cluster.
Aim 3 : Up-regulation of HMTases by chronic Cr(VI) exposure through oxidative stress.
Hexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants and exposure to Cr(VI) is a major environmental health concern, affecting millions of people in the United States as well many other countries. The goal of this study is to determine the epigenetic mechanism by which Cr(VI) exposure causes cancer.
|Wang, Zhishan; Wu, Jianjun; Humphries, Brock et al. (2018) Upregulation of histone-lysine methyltransferases plays a causal role in hexavalent chromium-induced cancer stem cell-like property and cell transformation. Toxicol Appl Pharmacol 342:22-30|