Prostate cancer is the most commonly diagnosed and the second leading cause of cancer death among American men. In 2013 the estimated new cases of prostate cancer and estimated prostate cancer deaths are 238,590 and 29,720, respectively. There are a significant proportion of organ-confined prostate cancers that have been 'successfully' treated experience disease recurrence and metastasize to other organs. At present, androgen deprivation therapy (ADT) is the mainstay of treatment for advanced/disseminated prostate cancer. However, the effectiveness of ADT is temporary, and tumors in the majority of patients eventually relapse and develop into CRPC. Unfortunately, there is no cure available for CRPC. It is of paramount importance to define new viable targets for development of novel therapeutics for CRPC in clinic.
A tumor suppression gene called PTEN is one of the most frequently mutated or deleted tumor inhibitory genes in human prostate cancers. In contrast, an oncogene termed EZH2 has been shown to be frequently overexpressed in human prostate cancers, especially in hormone therapy-resistant cancers. Although both PTEN and EZH2 are highly implicated in prostate cancer, PTEN-EZH2 functional interaction and the roles of these proteins in prostate cancer pathogenesis and hormonal therapy resistance are incompletely understood.
EZH2 is an enzymatic protein that has histone methyltransferase activity, through which it prohibits expression of many tumor suppression genes. We initially found that this function of EZH2 can be activated through a protein modification called phosphorylation, which was catalyzed by enzymes termed cyclin-dependent kinase 1 and 2 (CDK1/2) (Nat Cell Biol 12: 1108-1114, 2010). To understand the role of EZH2 phosphorylation in gene repression, we employed an advanced, unbiased, global approach, so-called RNA immunoprecipitation coupled sequencing (RIP-seq), to look for EZH2-associated large-size RNAs that do not encode protein, a novel class of factors that has emerged as a new, important aspect of cancer biology. We found that EZH2 binds to MALAT1, a cancer metastasis-related long non-coding RNA that has been implicated in many types of human cancer. Moreover, we showed that deletion or reduction of PTEN increases the level of total and phosphorylated EZH2 proteins and enhances EZH2-mediated repression of other genes in prostate cancer cells. Furthermore, an epigenetic independent function of EZH2 has been identified in hormone refractory prostate cancers. We demonstrated that this new function of EZH2 was enhanced by deletion of PTEN. Finally, we showed that treatment of therapy-resistant prostate cancer cells with the small molecule (chemical) inhibitor of EZH2 largely sensitizes therapy-resistant cells to be killed by docetaxel, a Food and Drug Administration (FDA)-approved chemotherapeutic agent that is currently in clinic use.
In this application, we will build upon our novel preliminary findings to understand the role of the RNA factor MALAT1 in EZH2 activation in prostate cancer, findings that will not only significantly advance our understanding of the molecular mechanism by which EZH2 drives prostate cancer, but also provide new opportunities for development of new therapeutics for prostate cancer treatment. Moreover, we will generate unique mouse models that will not only allow us to study the functional interrelationship between EZH2 and PTEN, but also could be used as a viable model for drug test in the future. Findings from this study will fundamentally advance our understanding of the biological significance of the functional connection between PTEN loss and activation of EZH2 in prostate cancer development and castration-resistant progression. Finally, our preliminary data demonstrated for the first time that the EZH2-specific inhibitor increases the therapeutic efficacy of the FDA-approved chemotherapeutic drug docetaxel in CRPC cells. We propose to exploit PTEN-null, androgen receptor-positive hormone therapy-resistant prostate cancer models to evaluate the therapeutic effect of the EZH2 inhibitor plus docetaxel on the growth of hormone-refractory tumors at the preclinic level (in mice). Findings from these animal studies will have significant impact on development of novel, mechanism-based therapeutic options for CRPC patients.
Overall, the new knowledge derived from the current study will lay the foundation for development of new therapeutic strategies that may improve the clinical outcome of hormone-refractory prostate cancer patients with deregulated PTEN and EZH2 pathways.
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