New epigenetic function
for extracellular Hsp90: 
heat-shocking the polycomb

Prostate cancer tops the charts as the most prevalent cancer in men and is second only to lung cancer as a cause of cancer-related death in men. In recent years, new diagnostics and treatment regimens have improved the prognosis of prostate cancer that is organ-confined. However, metastasis, the spread from the primary tumor location to distant organs, continues to be a key factor in prostate cancer mortality. Metastatic cancer cells are more aggressive and are often resilient to chemotherapy. This makes identifying the mechanisms that govern the switch from the localized to the aggressive phenotype in prostate cancers an important research goal. In a recent issue of the Journal of Biological Chemistry, investigators at the Medical University of South Carolina report a new epigenetic function for extracellular heat shock protein 90 and describe a novel signaling pathway driving prostate cancer metastasis.

The authors remind readers that a primary factor in cancer progression is the epithelial-to-mesenchymal transition, or EMT, a process whereby cells transition to a more aggressive state. EMT is a part of cancer’s invasion–metastasis cascade, a series of steps that consists of cells first invading adjacent tissue, then moving into blood vessels and finally achieving distant colonization.

The authors previously documented the role of the tumor-secreted eHsp90 in metastatic disease. eHsp90 is a chaperone protein that regulates the function of several genes implicated in cancer. But its exact mechanism remains undefined. This motivated Krystal D. Nolan, Jennifer Isaacs and colleagues at MUSC to investigate the link between eHsp90 and epigenetic players that are mostly members of the polycomb group of proteins. Their earlier study noted that eHsp90 is a key driver of EMT in prostate cancer. This one sought to define eHsp90’s signaling pathway.

Changes in genes regulating EMT often occur via epigenetic mechanisms that produce chromatin-structure modifications. The authors explored the regulation of EZH2, a key epigenetic regulator, by eHsp90. Their study used epithelial and mesenchymal cell lines. They used epithelial cadherin, a marker of the epithelial cells, as the target gene to study the EMT phenomenon. They found that the mesenchymal cell lines had substantially higher EZH2 and P-ERK protein levels than the epithelial cell lines.

Using a host of molecular biology techniques involving overexpression of eHsp90 as well as Hsp90- and ERK-specific inhibitors, the authors established the eHsp90–ERK signaling axis as mediating EZH2 activity. The study concludes with evidence of a dramatic change in appearance in the localized epithelial cells upon expression of eHsp90. Additionally, the team established the presence of EZH2 as a key contributor of the invasive phenotype.

These findings underscore the complex regulatory interplay between signaling molecules and EZH2, an integral component of the epigenetic machinery. Additionally, they highlight eHsp90 as a novel regulator of EZH2 and EMT in prostate cancer.

Kamalika Saha Kamalika Saha is a graduate student in the biochemistry and molecular biology department at the University of Maryland, Baltimore.