Abstract
Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated. In this report, we establish a link between HACE1 and the major stress factor, hypoxia-inducible factor 1 alpha (HIF1α). We find that HACE1 blocks the accumulation of HIF1α during cellular hypoxia through decreased protein stability. This property is dependent on HACE1 E3 ligase activity and loss of Ras-related C3 botulinum toxin substrate 1 (RAC1), an established target of HACE1 mediated ubiquitinylation and degradation. In vivo, genetic deletion of Rac1 reversed the increased HIF1α expression observed in Hace1–/– mice in murine KRasG12D-driven lung tumors. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner.
Highlights
These authors contributed : Busra Turgu, Fan Zhang
It has previously been suggested that HACE1’s tumor suppressor activity may be linked to cellular stress responses [3]. To further investigate this possibility, we examined HACE1 expression in HEK293 cells subjected to prototypical stress forms, namely short-term nutrient deprivation, hypoxia, endoplasmic reticulum (ER) stress, and γ-irradiation, as described in “Experimental procedures”
We show that hypoxia leads to marked increases in HACE1 at both the mRNA and protein levels, and surprisingly, that this is associated with loss of HIF1α protein
Summary
HIF1α is induced following the onset of hypoxic stress, where it transcriptionally activates a wide array of genes that are important for the re-programming of multiple pathways that impact cell survival under hypoxia, such as angiogenesis [27,28,29]. HIF1α induction under hypoxia requires activation of RAC1 [36,37,38,39]. In line with its putative tumor-suppressive role, the absence of HACE1 correlated with enhanced HIF1α protein levels in WT tissues compared to the patient-matched normal kidneys. Together, these data provide additional mechanistic insights into the tumor suppressor activity of HACE1, namely through the regulation of HIF1α
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