Cell-Type Independent MYC Target Genes Reveal a Primordial Signature Involved in Biomass Accumulation

Abstract

The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells.

An Overview of MYC and Its Interactome

“…Several classes of microRNAs were also found to be regulated by MYC (see Psathas and ThomasTikhonenko 2014). The notion emerged of a MYC "signature" encompassing groups of target genes devoted to growth and pluripotency (Kim et al 2010;Ji et al 2011). Analysis of target genes indicates that MYC binding results in hyperacetylation of histones, consistent with MYC's recruitment of HATs (Martinato et al 2008).…”

Links between metabolism and cancer

“…The ability of Myc to stimulate ribosome biogenesis genes distinguishes it as a unique E-box transcription factor capable of coupling the expression of metabolic genes with genes involved in cell mass accumulation (van Riggelen et al 2010;Ji et al 2011). Moreover, Myc uniquely activates genes driven by RNA polymerases I and III, which are required for the expression of ribosomal RNAs (Gomez-Roman et al 2006).…”

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

“…functions as a global controller of protein biosynthesis, with the regulation of components of the ribosome biogenesis machinery being one of the most consistent gene expression signatures associated with MYC activation (7,8). MYC transcriptional targets are important for key steps in the ribosome biogenesis process, including the synthesis of ribosomal RNAs (rRNA) and proteins (RP) as well as the expression of specific translation initiation factors [e.g., eukaryotic initiation factor 4E (eIF4E); refs.…”