Regulation of PTEN Dimerization and Activation by Atypical K27-Linked Ubiquitination for Prostate CancerTherapy
Abstract
Objective and Rationale: Prostate cancer (CaP) is the second leading cause of cancer-related deaths of men in the United States. However, there are still no effective targeting therapies for advanced CaP. We have exciting preliminary data showing that phosphatase and tensin homolog (PTEN) is atypical K27-linked poly-ubiquitinated and that this novel post-translational modification of PTEN leads to the disruption of its dimer formation, thus providing the first evidence regarding the underlying mechanism for PTEN dimerization. Our findings attribute a distinct role to atypical ubiquitination in CaP through the functional suppression of PTEN with important therapeutic implications. Therefore, targeting PTEN to alter its subcellular localization may offer a unique opportunity for prostate cancer therapy. However, the strategy and effectiveness of targeting PTEN to change its dimerization in the clinic remain largely unknown and require further examination. The current study aims to develop and characterize the therapeutic potential by targeting PTEN dimerization through inhibition of K27-linked ubiquitination to induce the robust activation of PTEN tumor suppressive function, thus offering another strategy for CaP therapy. Career Goals: My long-term goal is to pursue an academic position where I can continue my work in the translational research of human CaP. The proposed study would help me to gain the independence in my research and develop the critical thinking and knowledge necessary to accomplish my career goals. The main objective of this proposal addresses one Prostate Cancer Research Program overarching challenge: "Develop effective treatments for advanced prostate cancer" and would allow me to advance in my career toward becoming a productive and successful independent investigator in the field of prostate cancer research. Clinical Application and Contributions: PTEN is a key tumor suppressor gene in CaP. The manner in which PTEN is activated is an extremely important issue in tumor biology with huge possibilities for the discovery of new, targeted cancer therapies. Our studies could benefit many CaP patients in which PTEN dimerization and membrane localization is aberrantly lost in CaP, especially patients with advanced CaP, for which there are no therapeutic options currently available. Targeting E2/E3 to alter PTEN dimerization and activation could ultimately provide another novel therapy for CaP treatment. Understanding the underlying mechanisms of PTEN dimerization mediated by K27-linked ubiquitination will not only help us broaden the knowledge of prostate tumor biology but could also translate into PTEN dimerization targeting cancer therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610249
Entities
People
- Yu-Ru Lee
Organizations
- Beth Israel Deaconess Medical Center
- United States Army