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Publications of the Week

HACE1 Blocks HIF1α Accumulation under Hypoxia in a RAC1 Dependent Manner

By March 3, 2021No Comments

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This week, we profile a recent publication in Cell Reports from Dr. Poul Sorensen (pictured, above)
and Busra Turgu (pictured, below) at the University of British Columbia.

Can you provide a brief overview of your lab’s current research focus?

The Sorensen lab uses a combination of genetic, biochemical and proteomics approaches to identify proteins that are specifically altered in human tumours. Our main focus is on targeting aberrant signaling pathways that are dysregulated in high-risk childhood cancers, and how cancer cells use these pathways to adapt to acute stress such as hypoxia. We are particularly interested in how these cytoprotective pathways provide tumor cell fitness for metastatic capacity. We then use this information to identify novel strategies for therapeutic intervention to block tumor progression, including new targets for immunotherapy. The E3 ubiquitin-protein ligase HACE1, first discovered in our lab, is an example of such studies. We identified HACE1 as a tumor suppressor gene, first in pediatric Wilms’ tumor of the kidney, and then in other solid tumors. Genetic inactivation in mice led to dramatic increases in tumor incidence, particularly under different environmental stressors.

What is the significance of the findings in this publication?

Genetic inactivation of HACE1 in mice leads to the development of multiple late-onset tumors, including sarcomas, breast, lung, and other carcinomas, as well as lymphomas. However, the mechanism whereby HACE1 elicits its anti-tumorigenic effects remain incompletely characterized. Our new study illuminates a previously unrecognized link between HACE1, its primary E3 ligase target, the protein RAC1, and the oncogenic driver, hypoxia-inducible factor-1alpha (HIF1α). RAC1 is known to be pro-migratory in tumor cells, but links to HIF1α are unclear. Under hypoxia, HIF1α transcriptionally activates diverse genes important for the re-programming of pathways driving the adaptation, progression, and metastasis of cancer cells. We found that HACE1 reduces HIF1α accumulation by reducing active RAC1 levels. The absence of HACE1 correlates with enhanced HIF1α protein levels in tumor tissues compared to the patient-matched control tissues. Together, our data provide new mechanistic insights into the tumor suppressor activity of HACE1, namely by blocking the RAC1-dependent regulation of HIF1α in tumorigenesis.

What are the next steps for this research?

The next steps would be to understand the mechanistic details of how the HACE1-RAC1 axis regulates HIF1α stability, and whether other components are involved in this regulation. HIF1α is well-established to facilitate oncogenesis in a variety of cancers. Currently, several HIF1α inhibitors have been developed and used in preclinical and clinical studies. In future studies, it could be determined whether HACE1 deficiency can be used as a biomarker for sensitivity to the HIF1α inhibitors in the clinic. The HACE1-RAC1-HIF1α axis provides an attractive potential target for therapeutic intervention.

This research was funded by:

This work was supported in part by a CIHR Foundation grant [Grant#: FDN-143280], and by the British Columbia Cancer Foundation through generous donations from Team Finn and other riders in the Ride to Conquer Cancer. This was also supported by grants from IMBA, the Austrian Ministry of Sciences, the Austrian Academy of Sciences, a European Research Council (ERC) Advanced Grant, an Era of Hope Innovator award, and a Canada 150 Grant.


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