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  • Review Article
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bHLH–PAS proteins in cancer

Nature Reviews Cancer volume 13, pages 827–841 (2013)Cite this article

Subjects

Key Points

  • The basic HLH (helix–loop–helix)–PER–ARNT–SIM (bHLH–PAS) family of transcriptional regulators are characterized by an amino-terminal bHLH domain and PAS domains that are involved in dimerization, DNA binding and signal transduction.

  • The PAS domain is an evolutionarily conserved protein fold, which is often capable of binding to ligands or relaying signals. PAS domains also have important roles in mediating or restricting protein–protein interactions.

  • bHLH–PAS factors have diverse roles, which include sensing and responding to environmental pollutants (through the aryl hydrocarbon receptor (AHR)), hypoxic sensing (through hypoxia-inducible factor 1α (HIF1α) and HIF2α), circadian rhythm formation (through circadian locomotor output cycles kaput (CLOCK), neuronal PAS2 (NPAS2), brain muscle ARNT-like 1 (BMAL1), period circadian protein homologue 1 (PER1) and PER2), transactivation (through nuclear receptor co-activators (NCOAs)) of hormone signalling via nuclear receptors, appetite control (through single-minded homologue 1 (SIM1)), neurogenesis (through SIM1, SIM2 and NPAS3) and synapse formation (through NPAS4).

  • bHLH–PAS proteins, including AHR, HIFs and NCOAs, have important links with cancer and cancer metabolism. This has been shown using many mouse models and expression studies of human cancers.

  • Crosstalk between various bHLH–PAS family members can occur directly through competition for common partner proteins or DNA elements (for example, between HIF and SIM). This might promote tumour survival when these factors are misregulated.

  • Metabolites (kynurenine and NAD+) and oncometabolites (benzo[a]pyrene derivatives and (R)-2-hydroxyglutarate) can modulate or mediate the activity of several bHLH–PAS proteins (including the AHR, the HIFs and circadian rhythm factors CLOCK, BMAL1 and PER2) that have direct relevance to cancer.

  • bHLH–PAS structural resolution and high-throughput activity screens have facilitated the identification of small-molecule modifiers of bHLH–PAS factor activities, which may be useful as cancer therapeutics.

Abstract

Mammalian basic HLH (helix–loop–helix)–PER–ARNT–SIM (bHLH–PAS) proteins are heterodimeric transcription factors that sense and respond to environmental signals (such as pollutants) or to physiological signals (for example, hypoxia and circadian rhythms) through their two PAS domains. PAS domains form a generic three-dimensional fold, which commonly contains an internal cavity capable of small-molecule binding and outer surfaces adept at protein–protein interactions. These proteins are important in several pro-tumour and antitumour pathways and their activities can be modulated by both natural metabolites and oncometabolites. Recently determined structures and successful small-molecule screening programmes are now providing new opportunities to discover selective agonists and antagonists directed against this multitasking family of transcription factors.

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Figure 1: Roles and structures of class I and class II bHLH–PAS family members.
Figure 2: Ligand activation of AHR and control by negative feedback mechanisms.
Figure 3: 2-oxoglutarate-dependent enzymes feed into the hypoxic response and circadian rhythm pathways.
Figure 4: NAD+-dependent enzymes contribute to the hypoxic response and circadian rhythm pathways.
Figure 5: Competition between HIF1α and SIM2.

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  1. School of Molecular and Biomedical Science (Biochemistry) and the Centre for Molecular Pathology, University of Adelaide, 5005, South Australia, Australia

    David C. Bersten, Adrienne E. Sullivan, Daniel J. Peet & Murray L. Whitelaw

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Bersten, D., Sullivan, A., Peet, D. et al. bHLH–PAS proteins in cancer. Nat Rev Cancer 13, 827–841 (2013). https://doi.org/10.1038/nrc3621

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