Harnessing epigenetic therapy for cutaneous squamous cell carcinoma by targeting histone H3K9 methylation

Minneapolis Va Medical Center, Minneapolis MN

Investigators

Abstract

Keratinocyte carcinoma, including cutaneous squamous cell skin cancer (SCC), is the most common cancer in the United States. SCC disproportionately afflicts military personnel and Veterans due to excessive ultraviolet (UV) exposure during service. The VA Health Care System spends $137 million on KC treatment annually. In addition to the high treatment costs, over 15,000 Americans die from cutaneous SCC each year. Currently, the molecular drivers of SCC are incompletely characterized. Previous studies have primarily focused on the role of UV mutagenesis in causing SCC. However, UV-induced driver mutations are often found in sun-exposed non-malignant skin, suggesting that non-genetic mechanisms are also involved in UV-induced SCC pathogenesis. UV might promote SCC development by causing epigenetic alterations, but these epigenetic mechanisms and pathways are not clearly understood. In this application, we will investigate the role of the hairless (HR) gene as an epigenetic regulator in SCC pathogenesis. HR encodes a histone H3K9 demethylase and regulates target gene expression epigenetically. HR-regulated genes are often involved in cell proliferation, apoptosis, and cancer development. Mice with HR mutations exhibit a marked increase in UV- and chemical carcinogen-induced skin tumors. Furthermore, HR is frequently deleted and inactivated in human SCC tumors. The overall objective of this project is to investigate the mechanism of HR-regulated histone methylation in SCC growth and progression in humans. The overarching hypothesis is that HR is a novel tumor suppressor gene and that HR loss promotes SCC growth and progression through increased H3K9 methylation. We will employ innovative research strategies using both preclinical models and clinical specimens to rigorously test this project’s hypothesis in three Specific Aims. In Aim 1, we will investigate the impact of HR deficiency in human SCC clinical specimens. In Aim 2, we will test the effects of HR loss on cell proliferation, survival, and tumor growth in human keratinocytes and human SCC cells, as well as identify and validate HR-regulated epigenetic changes and downstream pathways. In Aim 3, we will investigate the role of histone H3K9 methylation in SCC pathogenesis and test if pharmacologic inhibition of H3K9 methylation inhibits UV-induced and chemical-induced SCC development in HR-deficient mice. Upon completing these studies, we expect to identify novel genetic and epigenetic determinants of SCC pathogenesis. If successful, this project will facilitate future clinical trials validating the utility and efficacy of histone methylation inhibitors in SCC prevention and treatment.