Oncogene c-Myc is frequently amplified and activated in human cancers. Deregulation of c-Myc protein has been shown to occur in 30% of all human cancers, especially in hematopoietic malignancies. As a transcription factor, c-Myc has been shown to regulate up to 15% of all human genome genes, controlling diverse cellular activities including cell cycle, ribosome biogenesis, protein synthesis, metabolism, apoptosis and angiogenesis. In this report, we provide evidence that the RNA helicase DHX33 is a critical downstream target of c-Myc. Myc binds to DHX33 upstream promoter region and stimulates its transcription. Elevated DHX33 protein is pivotal for c-Myc to drive tumor formation. Knockdown of DHX33 to basal levels in c-Myc overexpressing cells significantly reduced cell proliferation, cell migration and anchorage-independent cell growth in vitro and in vivo. Additionally, we found that DHX33 promotes MMP9, MMP14 and urokinase-type plasminogen activator (PLAU) transcription by directly binding to their promoters, thus promoting cancer cell migration. DHX33 protein was overexpressed in a certain subset of human non-Hodgkin's lymphoma tissues. Finally, knockdown of DHX33 significantly inhibits the development of Myc-induced acute myeloid leukemia. Overall, our results implicate the important role for DHX33 in Myc-induced cancer and point toward its potential therapeutic value in Myc driven cancers.
c RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. RNA polymerase I (Pol I) plays a central role in regulating cellular growth and proliferation (1). Eukaryotic cells contain hundreds of ribosomal DNA (rDNA) copies that occupy several different chromosomal locations (2). The production of rRNA can be divided into several steps, i.e., rRNA transcription, modification, and processing, all of which occur in the nucleolus (3, 4). The rate-limiting step is rRNA transcription (1, 5). On sensing of outside stimuli, a preinitiation complex comprised of the transcriptional factors upstream binding factor (UBF), SL1, TBP, Rrn3, and TTF assembles in the promoter region of rDNA. This complex then recruits RNA polymerase I to rDNA loci, and rRNA transcription starts (6-8). In mammalian cells, a single precursor rRNA transcript, 47S rRNA (14.3 kb), is transcribed from rDNA by the RNA polymerase I complex. This large polycistronic transcript encompasses 18S, 5.8S, and 28S rRNAs and includes several spacer regions, which are later processed into distinct rRNA species before assembly into preribosomal subunits (9).The transcriptional activity of Pol I is a fundamental determinant of cell proliferation capacity (3). In rapidly proliferating cells, rRNA production takes more than 50% of all nuclear transcriptional activity. In yeast cells, this percentage can reach more than 80% (10). As such, the tremendous energy consumption demands tight control.At the tissue level, cells attach to the extracellular matrix (ECM) through cell surface receptors termed integrins (11). Integrins are heterodimeric transmembrane receptors comprised of ␣ subunits and  subunits that bind to extracellular ligands, such as laminin, collagen, vitronectin, and fibronectin. Different combinations of the 18 ␣ subunits and 8  subunits confer specificity on the integrin-ECM interactions (12). After binding ...
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