# H3 histone oxidation is a new posttranslational modification linking heavy metal-induced metabolic changes and oncegenic epigenetic reprogramming

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $387,661

## Abstract

SUMMARY
Transcription stability enforces cellular identity and is tightly controlled by restrictions imposed on
both transcription factor function and target gene accessibility. Progression of cancer to
metastasis and multi-drug resistance requires fluid transcriptional programs that can explore
different genomic landscapes to enable clonal diversification and the origination of aggressive
and treatment resistant phenotypes. In this application, we explore the recent discovery that an
increase in the production of mitochondrial reactive oxygen species (mtROS), induced by heavy
metal contaminants (such as arsenic, lead and cadmium) promotes histone H3.1 oxidation,
eviction from nucleosomes and replacement by the oxidation-resistant variant H3.3. Oxidation-
induced H3 variant replacement opens silenced portions of chromatin thereby licensing epithelial
to mesenchymal transition (EMT) of ER+/PR+ breast cancer cells leading to the origination of
aggressive, therapy-resistant and metastatic phenotypes. Protecting H3.1 from oxidation (using
pharmacologic compounds) seem to block metal-induced EMT thereby improving chemotherapy
outcomes of metal-transformed xenograft tumors treated in mice. The fact that suppressing
nuclear ROS opposes metal-induced EMT also suggests that there is a key pathway for
transformation downstream of the many targets of heavy metals in cells that can be explored for
therapeutic gain. We suggest that metal-induced H3.1 oxidation by mitochondrial ROS is a new
regulatory link between metal-induced changes to the cancer cell metabolism and chromatin
remodeling controlling gene expression programs that enable breast cancer progression and drug
resistance acquisition. Hence, we believe that developing pharmacologic solutions to target this
pathway in the short term may represent a significant step forward towards mitigating grave
consequences of environmental health injustice disproportionally affecting low income breast
cancer patients.

## Key facts

- **NIH application ID:** 10775581
- **Project number:** 1R01ES035723-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marcelo G. Bonini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,661
- **Award type:** 1
- **Project period:** 2024-01-23 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10775581

## Citation

> US National Institutes of Health, RePORTER application 10775581, H3 histone oxidation is a new posttranslational modification linking heavy metal-induced metabolic changes and oncegenic epigenetic reprogramming (1R01ES035723-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10775581. Licensed CC0.

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