Targeting Transcriptional Co-repressor CoREST Complex in Melanoma

由染色质结构变化介导的基因转录模式的精确控制对细胞至关重要

Precise control of gene transcription patterns, mediated by chromatin structural changes, is essential for cell identity preservation that is disrupted in cancer cells. The CoREST complex, a multi-protein complex of histone-modifying enzymes, functions as a transcriptional co-repressor by facilitating formation of repressive chromatin. The CoREST complex contains two key histone modifying enzymes, lysine-specific histone demethylase 1 (LSD1) and histone deacetylase 1 and 2 (HDAC1 and HDAC2) held together by the CoREST scaffolding protein. These enzymes are typically up-regulated in cancer, suggesting the CoREST complex is a specific target for cancer therapy. The goal of this proposed study is to molecularly define the CoREST complex as a therapeutic target for cancer. We recently developed a small molecule inhibitor (corin2) of the CoREST complex. Corin2 is a dual inhibitor of LSD1 and HDACs1/2 in the CoREST complex and shows high potency anti-proliferative effects against many cancer cell types when screened against the NCI 60 panel, with particular efficacy versus human melanomas. Our preliminary data suggests that the CoREST complex activates c-MYC/E2F-stimulated target genes associated with cell cycle progression and proliferation. In contrast, genes encoding the BMP/SMAD membrane-bound ligand-dependent nuclear receptors, which are known for promoting cellular differentiation, are transcriptionally silenced by the CoREST complex. The anti- proliferative role of the TGF-β/BMP-mediated SMAD signaling pathway is well documented; however, this function is often lost in many cancer cells. Here, we hypothesize that the CoREST complex induces disruption of BMP/SMAD driven anti-proliferative/differentiation signals resulting in increased transcriptional activation of the MYC/E2F-dependent proliferation gene network. In this way, blocking the CoREST/MYC proliferative gene transcription network circuit is expected to be an effective strategy in cancer. To test this hypothesis, we will perform the following aims using melanoma as a target cancer model: 1) analyze genome-wide effects of corin2 to discover the CoREST complex target gene signature and its correlation with the c-MYC/E2F target transcription network, 2) define the role of the CoREST complex in BMP/SMAD signaling and the switch from a differentiation/tumor- suppressive phenotype to cell growth phenotype, 3) evaluate corin2 as an epigenetic anti-tumor agent by targeting the transcriptional regulatory mechanisms of the c-MYC/E2F transcription network. To accomplish these aims, we will use the small molecule CoREST inhibitor, corin2, as well as a series of chemically-related analogs; a genetically engineered mouse melanoma model; and human melanoma tissue specimens. These proposed studies will extend our knowledge of the chromatin repressive CoREST complex and its roles in regulating a cell proliferative gene transcription network. In this manner, this proposal will provide a mechanistic rationale for the development of a novel therapeutic strategy targeting epigenetic malignancy-associated pathways in melanoma and other cancers.