Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis

Abstract

The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci 1 . Recent work suggested that rather than up-and down-regulating selected groups of genes 1-3 , Myc targets all active promoters and enhancers in the genome (a phenomenon termed "invasion") and acts as a general amplifier of transcription 4,5 . However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during Bcell lymphomagenesis in mice, in cultured B-cells and fibroblasts. Consistent with long-standing observations 6 , we detected general increases in total RNA or mRNA copies per cell (hereby termed "amplification") 4,5 when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) 7,8 or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, while having the potential to interact with all active/poised regulatory elements in the genome 4,5,9-11 , Myc does not directly act as a global *

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

“…By establishing an epistatic relationship between MYC and CDK9 in cancer maintenance, we demonstrate that CDK9 is a key effector of MYC tumorpromoting activities. While our results do not exclude the possibility that other MYC functions also play a role (Sabo et al 2014;Walz et al 2014), they imply that transcription elongation mediated by MYC is essential for oncogene addiction and provide a strategy for therapeutically targeting this addiction in cancer patients.…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…Interestingly, it has been suggested recently that cMyc is posed to amplify all the extant expressed genes [35,36]. More recently, new evidence emerges to reveal that cMyc selectively fine-tunes expression of many important genes essential for cell growth and cancer progression [37][38][39]. All these results point to the enigmatic roles and underlying mechanisms for cMyc yet to be further elucidated under developmental or oncogenic circumstances.…”

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

“…35 Furthermore, it has been suggested that due to an invasion of low-affinity sites in promoters and enhancers, high levels of MYC can regulate additional gene expression programs, including those involved in apoptosis. 6,8 Last, complex formation with other transcriptional regulators such as MIZ1 can modulate transcriptional responses upon MYC overexpression. 6,7 It is likely that these quantitative changes in gene expression patterns represent essential molecular cues that allow differentiation between physiological and oncogenic levels of MYC and, ultimately, crossing of the apoptotic "threshold."…”

“…6,7 In addition, high levels of MYC can regulate genes by binding to distal enhancer elements. 8 In addition to promoting cell growth and transformation, deregulated expression of MYC sensitizes cells to apoptosis in multiple settings. [9][10][11] Consistently, impairment of apoptosis is a central feature during tumor progression and mutation or loss of apoptotic regulators accelerates MYC-induced tumorigenesis in different tissues in vivo.…”