Abstract
Simple SummaryB cell lymphomas mostly arise from malignant transformation of mature B cells and are typically driven by elevated levels of the oncoprotein Myc. Myc is a transcription factor regulating many protein-coding genes as well as the multicopy genes encoding ribosomal RNA (rRNA). The aim of this study was to understand, how Myc impacts rRNA genes in the course of B cell lymphomagenesis. Using a transgenic mouse model, we found that Myc and rRNA gene expression strongly increase upon tumor formation. Surprisingly, Myc also facilitates epigenetic silencing of a fraction of rRNA genes, thereby safeguarding genomic integrity in lymphoma cells. Together, the results show that Myc balances high activity and stability of rRNA genes. Perturbation of this equilibrium may be used as a therapeutic strategy.A major transcriptional output of cells is ribosomal RNA (rRNA), synthesized by RNA polymerase I (Pol I) from multicopy rRNA genes (rDNA). Constitutive silencing of an rDNA fraction by promoter CpG methylation contributes to the stabilization of these otherwise highly active loci. In cancers driven by the oncoprotein Myc, excessive Myc directly stimulates rDNA transcription. However, it is not clear when during carcinogenesis this mechanism emerges, and how Myc-driven rDNA activation affects epigenetic silencing. Here, we have used the Eµ-Myc mouse model to investigate rDNA transcription and epigenetic regulation in Myc-driven B cell lymphomagenesis. We have developed a refined cytometric strategy to isolate B cells from the tumor initiation, promotion, and progression phases, and found a substantial increase of both Myc and rRNA gene expression only in established lymphoma. Surprisingly, promoter CpG methylation and the machinery for rDNA silencing were also strongly up-regulated in the tumor progression state. The data indicate a dichotomous role of oncogenic Myc in rDNA regulation, boosting transcription as well as reinforcing repression of silent repeats, which may provide a novel angle on perturbing Myc function in cancer cells.
Highlights
Cancer formation is a multistage process comprising the accumulation of molecular lesions that override cellular growth control
The data indicate a dichotomous role of oncogenic Myc in rDNA regulation, boosting transcription as well as reinforcing repression of silent repeats, which may provide a novel angle on perturbing Myc function in cancer cells
Abrogation of levels during lymphomagenesis, we argue that Myc promotes ribosomal RNA (rRNA) synthesis, and silencing compromises rDNA integrity, constituting a so far unexplored vulnerability of Mycensures nucleolar remodeling complex (NoRC)-dependent rDNA silencing
Summary
Cancer formation is a multistage process comprising the accumulation of molecular lesions that override cellular growth control. Research over the last decades has uncovered several cellular capabilities that are typically acquired during carcinogenesis and are, coined “hallmarks of cancer” [1,2,3]. One of these hallmarks, i.e., sustained proliferative signaling, can be viewed as the most fundamental characteristic of cancer cells. A key factor integrating proliferation signals and transmitting them to target genes is the proto-oncoprotein Myc. Myc is a potent growth-promoting factor and the Myc gene is overexpressed in most cancers, either due to chromosomal translocation, amplification, or transcriptional dysregulation [4,5]. The first observation that Myc overexpression drives human carcinogenesis was made in Burkitt lymphoma, an aggressive
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