HIF-1α induces cell cycle arrest by functionally counteracting Myc

Abstract

Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF‐1α, a basic helix–loop–helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF‐1α for hypoxia‐induced growth arrest and activation of p21cip1, a key cyclin‐dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21cip1 activation has been elusive. Here we demonstrate that HIF‐1α, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21cip1. The HIF‐1α antagonism is mediated by displacing Myc binding from p21cip1 promoter. Neither HIF‐1α transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF‐1α. In keeping with its antagonism of Myc, HIF‐1α also downregulates Myc‐activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF‐1α pathway, which regulates a distinct group of Myc target genes in response to hypoxia.

Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

“…HIF-1a/HIF-1b heterodimer acts as a transcription factor through binding to the hypoxia-responsive element in the cis-acting sequences (Semenza, 2000). More recently, nontranscriptional activity of HIF-1a protein was also proposed (Koshiji et al, 2004). To understand whether transcription action of HIF-1a protein is required for its differentiation induction, the expression of HIF-1b was suppressed by shRNAs with reduced expression of HIF-1-targeted genes.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…Intriguingly, however, HIF and MYC are traditionally considered to have antagonistic effects in the hypoxic cell. Indeed, HIF was found to counteract MYC by various underlying mechanisms including the induction of MXI1, another MYC antagonist, competition with MYC for promoter binding or promoting its proteasomal degradation [45,46]. This paradox may reflect the different models studied so the biological relevance of the miR-210-promoted MYC functions in the regulation of HIF requires further clarification.…”

Metabolic reprogramming of the tumor

“…Strikingly, TP53 knockout (Ravi et al, 2000) and c-MYC overexpression (Shim et al, 1997) also increase HIF-1 activity. Although HIF-1a is overexpressed in a wide array of human cancers (Semenza, 2003) and fosters their aggressiveness (Akakura et al, 2001), it induces cell-cycle arrest in normal cells through MYC repression (Koshiji et al, 2004). Interestingly, c-MYC overexpression results in cooperation between MYC and HIF-1, inducing a shift from OXPHOS to lactic fermentation (Kim et al, 2007).…”

“…Mitochondrial defects in normal cells lead invariably to HIF-1a stabilization: while succinate dehydrogenase and fumarate hydratase dysfunction leads to prolyl hydroxylase inactivation by their substrates that leak into the cytosol (King et al, 2006), ETC blockers enhance mitochondrial ROS production (Varum et al, 2009), which have the same effect. HIF-1 activity alone retards normal cell proliferation (Koshiji et al, 2004). It needs to be combined with MYC or perhaps other oncogenic protein over-activity in order to promote the cancer metabolic shift (Kim et al, 2007) and growth.…”