Histone methyltransferases (HMTases) are chromatin modifiers that play an important role in normal development as well as in diseases such as cancer. Following the discovery by our group that EZH2 is overexpressed and associates with prostate cancer progression and poor prognosis (1), it has become the most well-studied HMTase in cancer with multiple research groups and pharmaceutical companies in pursuit of developing EZH2 inhibitors for clinical use. However, direct targeting of EZH2 is deemed problematic since it also has a role in stem cell maintenance and acts as a tumor suppressor in myeloid diseases. More recently, our transcriptome and protein expression analysis across multiple cancers including primary and metastatic prostate tumors revealed overexpression of another HMTase, MMSET, that paralleled EZH2 expression, function and clinical attributes (2). EZH2, which is associated with gene silencing mediated through histone H3K27 trimethylation, was found to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation associated with active transcription. Given the high expression and functional significance of MMSET as an effector of EZH2-mediated oncogenesis as well as the observation that MMSET plays a critical role in prostate cancer by regulating AR signaling and gene expression, we hypothesize that MMSET potentially represents an important therapeutic target in prostate cancer. In an effort to therapeutically target MMSET we have identified a lead probe compound, 3-hydraxino-2-quinoxalinethiol (MCTP39), a thiol group containing isomer of hydralazine (a known epigenetic drug), that was found to attenuate MMSET enzymatic activity in vivo. Further, MCTP39 was shown to inhibit growth and invasive properties specifically of cancer cell lines that overexpress MMSET. Here, we propose to carry out the following Specific Aims: 1) Integrative functional study of MMSET in prostate cancer; 2) Elucidation of the role of MMSET in AR signaling; 3) Characterization of a lead MMSET inhibitor compound MCTP39. Successful completion of the Aims outlined in this proposal will improve understanding of the role of MMSET and its importance in AR-mediated prostate cancer progression, and may yield a promising small molecule inhibitor that could be further developed for clinical use. The proposed projects and the supporting preliminary data were conceived based on the applicant's original ideas. The cross-disciplinary environment provided by Dr. Chinnaiyan at the Michigan Center of Translational Pathology, which has vast experience applying high-throughput technologies and bioinformatics approaches for studying the mutational landscape of cancer and identifying associated biomarkers and therapeutic targets, serves as an ideal environment for supporting the applicant's scientific career goals. This is exemplified by the applicant's extensive preliminary data that has led to multiple first author and co-author papers in high impact journals. Dr. Chinnaiyan has extended his full support towards the applicants' career goals and has encouraged him to transfer these projects to his independent lab in the future. Overall, an NIH Pathway to Independence Award will be indispensable for the applicant to transition into an independent investigator in the field of cancer biology specifically in translating genome-based discoveries into clinical applications.
The histone methyltransferase MMSET is overexpressed in prostate cancer and correlates with disease progression. The exact molecular mechanism of how MMSET executes its oncogenic function and what role it plays in AR-mediated transcription, which is a hallmark of castration-resistant prostate cancer, is not clear. This proposal addresses both these important questions and in addition proposes to evaluate a lead MMSET inhibitor compound for utility in prostate cancer therapy.
|Asangani, Irfan A; Wilder-Romans, Kari; Dommeti, Vijaya L et al. (2016) BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer. Mol Cancer Res 14:324-31|