Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles

Abstract

In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.

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."…”

“…6,8 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." 36 We demonstrated previously that association with MIZ1 and subsequent repression of target genes of the SRF transcription factor are required to induce apoptosis in response to oncogenic MYC levels.…”

“…[3][4][5] In contrast, deregulation of MYC activates and represses more restricted sets of target genes during tumorigenesis. 6 For example, complex formation with MIZ1 (ZBTB17), which occurs predominantly at oncogenic MYC levels, mediates binding to low-affinity sites and shifts the direction of transcriptional responses at these "newly acquired" target genes toward repression. 6,7 In addition, high levels of MYC can regulate genes by binding to distal enhancer elements.…”

“…6 For example, complex formation with MIZ1 (ZBTB17), which occurs predominantly at oncogenic MYC levels, mediates binding to low-affinity sites and shifts the direction of transcriptional responses at these "newly acquired" target genes toward repression. 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.…”

Concepts to Target MYC in Pancreatic Cancer

“…MYC alone is sufficient to initiate tumors and to drive tumor progression in the pancreas in vivo (5,(7)(8)(9)(10). Furthermore, compelling evidence exists that MYC is an essential downstream effector of oncogenic KRAS in the pancreas (11)(12)(13)(14). MYC expression is controlled at several layers in PDAC (15).…”