Cancer metastasis associated with the progression of prostate cancer (PCa) is the second leading cause of cancer death in men. Metastatic progression is commonly associated with initiation of the epithelial to mesenchymal transition (EMT) developmental genetic program. A fundamental hallmark of EMT is the suppression of the EMT gatekeeper E-cadherin, and subsequent loss of epithelial properties such as cuboidal epithelial morphology. This occurs concomitant with a cellular conversion towards mesenchymal features including proteolytic activity, markedly increased cell motility, invasion, and metastatic behavior. Thus, the expression of E-cadherin, and its regulation of epithelial junctional complexes, is critical for the maintenance of cell-cell contact, epithelial polarity, and for restraining tumor dissemination. EMT is regulated by coordinated signaling and epigenetic events. In particular, upregulation of components of the chromatin remodeling polycomb repressor complexes in metastatic cancers, such as Enhancer of Zeste Homolog 2 (EZH2), correlates with poor prognosis. EZH2 overexpression is a widespread occurrence in PCa and is proposed to contribute to treatment failure and lethality. EZH2 is a histone methyltransferase that mediates the suppression of tumor suppressor genes to facilitate a pro-tumorigenic genetic profile. EZH2 has been shown to both suppress E-cadherin and to promote EMT events, indicating this as one key mechanism for its tumorigenic activity. Although the role of EZH2 as a mediator of cancer progression is well known, the tumor secreted factors regulating its expression remain unknown. We have recently shown that extracellular Hsp90 (eHsp90) is a novel initiator of EMT events. Clinically, eHsp90 is preferentially detected in patient serum from those afflicted with various primary and metastatic cancers, including PCa. Additionally, eHsp90 appears to function as a critical pro-metastatic factor in preclinical tumor models. In particular, eHsp90 suppresses E-cadherin expression and function, promotes a mesenchymal morphology, and increases cell motility and proteolytic activity. I have recently found that eHsp90 upregulates EZH2 expression in an ERK-dependent signaling pathway, and strikingly, both ERK signaling and EZH2 expression are essential for eHsp90 mediated suppression of E-cadherin. Further evidence that eHsp90 subverts EZH2 function is demonstrated by the finding that eHsp90 promotes the recruitment of EZH2 to the E-cadherin reporter, indicating a mechanistic basis for E-cadherin suppression. We therefore hypothesize that eHsp90 promotes PCa tumor progression via activation of ERK, upregulation of EZH2 and suppression of E-cadherin, thereby initiating tumorigenic EMT events. To test this hypothesis, I will determine how eHsp90 upregulates EZH2 and alters its recruitment to promote tumorigenesis and metastasis in prostate cancer both in vitro and in vivo. These studies will require me to develop a diverse range of technical skills and collaborate with experts in various fields. This training wll foster my development as an independent researcher and prepare me for a career in academic research.
Prostate cancer is the second leading cause of cancer deaths in men. This lethality is primarily due to development of metastatic disease. Identification of mechanisms in metastatic progression can lead to better monitoring and development of novel therapeutics that more effectively target this mechanism.
| Nolan, Krystal D; Kaur, Jasmine; Isaacs, Jennifer S (2017) Secreted heat shock protein 90 promotes prostate cancer stem cell heterogeneity. Oncotarget 8:19323-19341 |
| Nolan, Krystal D; Franco, Omar E; Hance, Michael W et al. (2015) Tumor-secreted Hsp90 subverts polycomb function to drive prostate tumor growth and invasion. J Biol Chem 290:8271-82 |
| Hance, Michael W; Nolan, Krystal D; Isaacs, Jennifer S (2014) The double-edged sword: conserved functions of extracellular hsp90 in wound healing and cancer. Cancers (Basel) 6:1065-97 |
| Hance, Michael W; Dole, Krystal; Gopal, Udhayakumar et al. (2012) Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J Biol Chem 287:37732-44 |
