# THE EPIGENETIC MECHANISM OF HEXAVALENT CHROMIUM CARCINOGENESIS

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $224,975

## Abstract

PROJECT SUMMARY/ABSTRACT
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...

## Key facts

- **NIH application ID:** 10373379
- **Project number:** 7R01ES026151-07
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Chengfeng Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,975
- **Award type:** 7
- **Project period:** 2021-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373379

## Citation

> US National Institutes of Health, RePORTER application 10373379, THE EPIGENETIC MECHANISM OF HEXAVALENT CHROMIUM CARCINOGENESIS (7R01ES026151-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10373379. Licensed CC0.

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