Molecular mechanisms by which interferon regulatory factor-8 (IRF-8), a member of the IRF family of transcription factors, suppresses tumor progression of both hematopoietic and nonhematopoietic malignancies
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It is well recognized that deregulation of certain transcription factors is indispensable during tumor progression. Identification and characterization of these genes are therefore fundamental requirements to inhibit the neoplastic process. Interferon regulatory factor 8 (IRF-8) is one such transcription factor that was originally identified as a master regulator of immune development, lineage selection and apoptotic regulation. It was later recognized as a tumor suppressor gene in hematopoietic cancer. IRF8 also inhibits non-hematopoietic cancer progression by sensitizing tumors to apoptotic death. Subsequently, it became apparent that IRF-8 expression was repressed in diverse types of hematopoietic and solid tumors. A fundamental gap in the IRF-8 field is, how tumors undermine IRF-8-expression and what the molecular targets of IRF-8 are which compromise tumor progression. My thesis addresses the interplay between IRF-8 and tumor and attempts to answer these questions. The overarching hypothesis of my thesis is that tumors employ distinct mechanisms to downregulate IRF-8, the transcriptional activities of which counteract tumor malignancy. To answer the specific questions we explored multiple tumor models. We utilized chronic myeloid leukemia (CML) as a prototypical hematopoietic cancer. In CML, BCR-ABL fusion protein acts as an oncogene that initiates uncontrolled proliferative signaling through STAT5. We also used a chemically induced sarcoma model, CMS4, a prototypical non-hematopoietic cancer. To summarize our findings, we observed that: 1) IRF-8 is strongly diminished in CML-cells by STAT5 via a DNA binding interaction. This could be rescued by inhibitor molecules of BCR-ABL or STAT5 suggesting a BCR-ABL-STAT5-IRF-8 network targetable through therapeutic intervention. 2) Deacetylation of the IRF-8 gene associated histones emerged as a potential repression mechanism in solid tumors. Efficacy of HDACi-drugs could be dependent on the functional status of IRF-8 in a STAT1-dependent manner indicating the importance of IRF-8 in anti-tumor therapies. 3) Matrix metalloproteinase three (MMP3) is a transcriptional target of IRF-8 in multiple solid tumor models. Although MMP3 is linked to tumor initiation, the role of MMP3 beyond this stage has not been addressed. We demonstrated that MMP3 governs progression and metastasis of tumor through a novel IRF-8-MMP3 axis. Collectively, these studies yield a better understanding of the interplay between IRF-8 and cancer development. These findings, in conjunction with previous work, also implicate IRF-8 as a potential therapeutic and prognostic tool.