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

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 providing new first-in-kind therapeutic solutions for breast cancer patients.