DNA damage players are linked to HIF-1α/hypoxia signaling

HIF-1α/hypoxia signaling regulates diverse biologic processes, such as glycolysis, angiogenesis, and invasion leading to promoting cancer progression, metastasis and therapy resistance.¹ Understanding the mechanisms by which HIF-1α/hypoxia signaling is regulated may provide the new paradigms and strategies for cancer therapy and overcoming drug resistance. VHL is a well-characterized E3 ligase component that serves as a critical tumor suppressor by driving HIF-1α ubiquitination and degradation.¹ Inactivation of VHL due to the loss of VHL expression or its inactivated mutations is often observed in cancers such as renal carcinomas, rendering HIF-1α accumulation and hypoxia signaling activation to promote cancer phenotypes.¹ Since VHL is commonly inactivated and/or lost in advanced cancers, it is technically challenging to develop a good strategy to target VHL for cancer therapy. Therefore, finding druggable regulators that positively maintain HIF-1α stability and nuclear translocation in a VHL-independent manner can provide promising paradigms and strategies for targeting cancers with activation of HIF-1α/hypoxia signaling.

Phosphorylation of H2AX at S139 known as γH2AX occurred during double stranded DNA breaks not only serves as a DNA damage marker, but also plays a critical role in mediating homologous DNA repair.² H2AX is therefore thought to be a tumor suppressor by maintaining genomic stability.² Interestingly, hypoxia is known to induce γH2AX formation without causing DNA damage through a mechanism that is yet to be determined.³ Whether or not γH2AX accumulation under a hypoxia challenge plays any role in HIF-1α/hypoxia signaling remains unclear. A recent study from Lin's group has surprisingly revealed a crucial role of γH2AX in HIF-1α/hypoxia signaling.⁴ γH2AX triggered by active ATM kinase during hypoxia interacts with HIF-1α to maintain its stability and nuclear accumulation, thereby facilitating HIF-1α/hypoxia signaling activation. γH2AX does so by preventing the interaction between HIF-1α and 20S proteasome component α4, in turn promoting expression of hypoxia target genes critical for glycolysis, survival and invasion⁴ (Fig. 1). While H2AX regulates DNA damage signaling, its role in HIF-1α/hypoxia signaling does not seem to depend on its classical functions in mediating DNA damage response.⁴

Figure 1.

The TRAF6-ATM-H2AX axis regulates HIF-1α/hypoxia signaling.

Apart for γH2AX induction, hypoxia also triggers monoubiquitination of H2AX at Lys 119/120, which serves as a critical step for hypoxia-mediated γH2AX formation by recruiting active ATM to H2AX.⁴ Monoubiquitination of H2AX is initiated by E3 ligase TRAF6, which is induced and activated by hypoxia and plays a crucial role in HIF-1α/hypoxia signaling activation by promoting HIF-1α stability and nuclear accumulation.⁴ TRAF6 and H2AX are amplified in a variety of cancer types, and TRAF6-mediated γH2AX is significantly correlated with HIF-1α expression and hypoxia gene signatures and predicts poor survival outcome.⁴ Further study using in vivo mouse tumor models showed that TRAF6-mediated monoubiquitination of H2AX and γH2AX promote breast cancer progression and metastasis.⁴ This study extends the known role of TRAF6 and H2AX from Akt signaling activation⁵ and DNA damage signaling,² respectively, to HIF-1α/hypoxia signaling. Thus, the TRAF6-ATM-H2AX network serves as a novel signaling module critical for HIF-1α/hypoxia signaling and cancer progression and metastasis (Fig. 1).

Several outstanding questions remain to be addressed. Although ATM is activated by hypoxia and is crucial for HIF-1α/hypoxia signaling, it is puzzling about how hypoxia triggers ATM activation since DNA damage is not induced by hypoxia.⁴ It is likely the induction of reaction oxygen species (ROS) by hypoxia may mediate ATM activation, since hypoxia induces ROS that is known to trigger ATM activation.⁶ In addition to being activated by cytokines and growth factors,⁵ TRAF6 E3 ligase is also activated by hypoxia through an unknown mechanism.⁴ It will be interesting to know whether ROS is also involved in hypoxia-mediated TRAF6 activation. Moreover, as H2AX interacts with HIF-1α, it will be of significance to determine whether H2AX is recruited to the promoter region of HIF-1α target genes and works in concert with HIF-1α to drive expression of HIF-1α target genes. Finally, since HIF-1α/hypoxia signaling drives stemness and drug resistance, it will be critical to determine whether TRAF6-ATM-H2AX signaling network maintains cancer stem cell traits and their self-renewal capability, in turn promoting cancer metastasis and drug resistance. Nevertheless, this new study not only advances our current understanding of HIF-1α/hypoxia signaling regulation, but also offers novel strategies for targeting cancers with elevated HIF-1α/hypoxia signaling. We propose that targeting TRAF6-ATM-H2AX signaling network may be a promise strategy for cancer therapy.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.