A small regulatory protein can be found not only in all humans, animals, plants and fungi, but in each and every eukaryotic cell. Following the discovery of these ubiquitous proteins in 1974, researchers aptly named them ubiquitin. Enzymes and/or ligases (enzymes that catalyze the formation of chemical bonds), allow ubiquitins to bind to substrate proteins. This process, known as ubiquitination, can initiate or prevent protein interactions, denote them for degradation and alter their activity and cellular location.
Aberrant ubiquitination may play an important role in tumorigenesis. At the core of solid tumors, hypoxia-inducible factor 1α (HIF-1α) is induced (by hypoxia) and allows cancer cells to adapt to the lack of oxygen. The accumulation of HIF-1α can also transcribe a number of genes well-known to be involved in cancer. Therefore, HIF-1α is an attractive, albeit difficult-to-pinpoint, therapeutic target in cancer. Researchers—from Brown University and Lifespan Cancer Institute—previously observed the stabilization of HIF-1α by the protein coding gene cyclin-dependent kinases CDK1. They further proposed that CDK4 may also be an HIF-1α stabilizer. However, the mechanism of HIF-1α’s regulation by CDK4 has yet to be fully elucidated.
“Till now, development of therapies targeting HIF-1α remains hindered. Therefore, it is imperative to explore the mechanism of HIF-1α regulation in cancer cells and investigate new possibilities to therapeutically target HIF-1 signaling.”
In 2021, the same team conducted a new study further investigating the molecular mechanisms of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors in colorectal cancer. Their priority research paper was published as the cover of Oncotarget’s Volume 12, Issue 20, and entitled, “Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase.”
Full blog - https://www.oncotarget.org/2021/09/30/new-study-protein-analysis-reveals-novel-role-of-enzyme-in-cancer/
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DOI - https://doi.org/10.18632/oncotarget.28081
Full text - https://www.oncotarget.com/article/28081/text/
Correspondence to - Wafik S. El-Deiry - wafik@brown.edu
Keywords - Smurf2, CDK4/6 inhibition, HIF1alpha, hypoxia, cancer therapy
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