HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation

Abstract

O(2) deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia-inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O(2). However, acting in concert these transcription factors reprogram metabolism, protein synthesis, and cell cycle progression, to "fine tune" adaptive responses to hypoxic environments.

Figure 1. Schematic of HIF and c-Myc effects on carbon metabolism

Both HIF and c-Myc act on multiple targets to regulate carbon utilization. HIF targets are shown in blue, c-Myc targets in red, and targets regulated by both HIF and c-Myc in green. Arrows are included to designate effects on flux through cellular pathways, with blue arrows showing pathways promoted by HIF, red arrows those promoted by c-Myc and green arrows by both.

Figure 2. Hypoxic, HIF and c-Myc effects on protein translation

While c-Myc promotes ribosome biogenesis and expression of components of the translational machinery, hypoxia and HIFs modulate growth factor signaling pathways that normally upregulate translation. c-Myc targets and c-Myc promoted processes are highlighted in red, while direct HIF targets and hypoxia promoted processes are shown in blue.

Figure 3. Acute and chronic HIF effects on c-Myc transcriptional activity

When HIF-1α is induced (A), it acts immediately to disrupt c-Myc complexes. By inducing Mxi, it also causes transcriptional repression of some c-Myc target genes. Conversely (B), HIF-2α increases c-Myc transcriptional activity at specific targets, while inhibiting the expression of others via Mxi. By increasing c-Myc/Max interactions, HIF-2α promotes c-Myc mediated activation or repression of Cyclin D2, p21 and p27. However, Mxi induction inhibits expression of other c-Myc activated targets (e.g. CAD and ODC).