# MGMT DOWN-REGULATION IN THE CARCINOGENICITY OF HEXAVALENT CHROMIUM

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $338,879

## Abstract

PROJECT SUMMARY/ABSTRACT
Hexavalent chromium [Cr(VI)] exposure causes multiple toxic effects in humans. The main concern of Cr(VI)
toxicity is its carcinogenicity as Cr(VI) is one of the most well-recognized environmental and occupational
carcinogens causing lung and other cancer in humans. While it is under active study, the mechanism of Cr(VI)
carcinogenicity remains elusive. Previous studies showed that Cr(VI) exposure causes genotoxic effects, which
are thought to play important roles in Cr(VI) carcinogenicity. On the other hand, studies also showed that Cr(VI)
exposure dysregulates epigenetics such as increased DNA methylation and abnormal histone posttranslational
modifications. However, it remains to be determined how dysregulated epigenetics contributes to Cr(VI)
carcinogenicity and if Cr(VI)-caused epigenetic changes play a role in its genotoxic effect. Our preliminary studies
showed: (i) Chronic Cr(VI) exposure increases the levels of histone H3 repressive methylation marks (H3K9me2
and H3K27me3) and their related histone methyltransferases (HMTases) (G9a, SUV39H1, and EZH2). (ii) Up-
regulation of HMTases play a causal role in Cr(VI)-induced cancer stem cell (CSC)-like property and cell malignant
transformation. (iii) Chronic Cr(VI) exposure down-regulates the expression of O6-methylguanine DNA
methyltransferase (MGMT), a key gene in DNA repair network; and MGMT down-regulation plays a causal role
in Cr(VI)-induced cell transformation. (iv) The level of O6-methylguanine (O6-MeG), a highly mutagenic DNA
lesion, is significantly increased in Cr(VI)-transformed cells; but stably expressing MGMT greatly reduces
Cr(VI) exposure-induced O6-MeG. (v) Cr(VI) exposure also significantly decreases the level of MGMT but
increases O6-MeG level in mouse and human lung tissues. (vi) Stably knocking down HMTases G9a or
SUV39H1 significantly increases MGMT level but reduces O6-MeG level in Cr(VI)-exposed cells. (vii) Cr(VI)-
transformed cells display impaired DNA damage repair capacity but stably expressing MGMT significantly
reduces chronic Cr(VI) exposure-caused DNA damage repair deficiency. And (viii) Treatment with a natural
compound dihydromethysticin (DHM) is capable of increasing MGMT level and reducing O6-MeG level in Cr(VI)-
transformed cells. (viii) We generated a conditional and lung specific MGMT expression transgenic mouse model.
Based on these findings from our preliminary studies and that from literature reports, our central hypothesis is that
up-regulation of HMTases by chronic Cr(VI) exposure down-regulates the expression of MGMT leading to
increased level of highly mutagenic DNA lesion O6-MeG and promoting Cr(VI) carcinogenesis. Three aims are
proposed: Aim 1 will determine the mechanism by which chronic Cr(VI) exposure causes MGMT down-
regulation. Aim 2 will determine the role of MGMT in C(VI)-induced lung tumorigenesis using a conditional and
lung specific MGMT expression transgenic mouse model. And Aim 3 will determine the protect...

## Key facts

- **NIH application ID:** 10414567
- **Project number:** 7R01ES029496-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Zhishan Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,879
- **Award type:** 7
- **Project period:** 2019-09-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414567

## Citation

> US National Institutes of Health, RePORTER application 10414567, MGMT DOWN-REGULATION IN THE CARCINOGENICITY OF HEXAVALENT CHROMIUM (7R01ES029496-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10414567. Licensed CC0.

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