Oxidative stress is a consequence of an imbalance between the generation of reactive oxygen species (ROS) and the detoxification of reactive intermediates by cytoprotective systems. Severe oxidative stress causes cancer cell death, while chronically low levels of elevated ROS promote cell proliferation, angiogenesis, and tumorigenesis. Understanding how cellular networks regulate ROS production and clearance, as well as the mechanism by which ROS regulate proliferation and cell death, are key to the development of therapeutic agents for cancer.
Sulforaphane (SFN), a thiocyanate enriched in cruciferous vegetables, is undergoing evaluation in clinical trials as a means to treat or prevent various human diseases, including breast cancers. However, our knowledge of the molecular mechanisms whereby SFN achieves its anti-tumorigenic activity is incomplete. In addressing this critical “gap in knowledge”, we demonstrate that SFN targets promyelocytic leukemia protein (PML), triggering its redistribution from the nucleus to the cytoplasm. PML is an established tumor suppressor that has recently been associated with the development and progression of human tumors. Although PML is a well-studied protein at the nexus of many pathways, the fundamentals governing the nucleocytoplasmic distribution of PML are still missing. Importantly, we find that SFN modifies key cysteine residues in PML to reduce its nuclear abundance. Studies of PML Cys to Ala mutations demonstrated that these SFN-targeted Cys residues are critical for PML functions. Together, our studies support a model in which PML is a SFN direct target that mediates SFN-induced cell cytotoxicity.
Hung-Ying Kao is currently a Professor in the Department of Biochemistry at Case Western Reserve University (CWRU). He is also an Adjunct Professor in the Comprehensive Cancer Center, the University Hospitals Cleveland Medical Center, and the Cleveland Clinic. My research program aims to dissect signaling and transcriptional regulation in human health and diseases, including the role of tumor suppressors and oncoproteins in breast cancer (BC). He have been broadly trained from yeast genetics to biochemistry, and vertebrate molecular and cell biology, with specific training on the regulation of gene expression by nuclear hormone receptors (NRs). His lab has longstanding interests in studying transcriptional regulation by NRs, including estrogen receptor (ER), as well as the role of promyelocytic leukemia protein (PML) in BC cells. His lab has also collaborated in the identification of a novel interface between the ER DNA-binding domain (DBD) and the ligand-binding domain (LBD).