Oncotarget: Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase

Oncotarget published "Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase" which reported that gene knockdown of SMURF2 increased basal expression of HIF-1 even in the presence of Ro3306 or two different CDK4/6 inhibitors, palbociclib and abemaciclib.

Overexpression of Smurf2 inhibited expression of HIF-1 and enhanced HIF-1 ubiquitination in normoxia. Proteasome inhibitor MG-132 partially rescued HIF-1 expression when Smurf2 was overexpressed. Smurf2 overexpression also inhibited HIF-1 expression level in two other cell lines, SW480 and VHL-deficient RCC4.

Overexpression of SMURF2 mRNA is correlated with improved disease-free survival and overall survival in clear cell renal cell cancer. The authors' results unravel a previously unknown mechanism involving Smurf2 for HIF-1 destabilization in CDK4/6 inhibitor-treated cells, thereby shedding light on VHL-independent HIF-1 regulation.

Dr. Wafik S. El-Deiry from The Brown University as well as The Lifespan Cancer Institute said, "Angiogenesis in solid tumors often results in abnormal vasculature."

Figure 8: Proposed model of Smurf2-mediated HIF-1α regulation. (A) Smurf2 interacts with HIF-1α and targets it for ubiquitination, which results in HIF-1α destabilization. (B) Distinct HIF-1α phosphorylation peptides revealed by proteomics in control and palbociclib-treated groups.

The lack, leaking, distortion and occlusion of blood vessels impedes oxygen delivery. Oxygen consumption by uncontrolled tumor growth adds onto the oxygen deficiency. The intratumoral hypoxia creates a specific microenvironment that activates the adaptive responses mediated by hypoxia-induced factor 1. HIF-1 is the alpha subunit of HIF-1, the transcription factor that modulates the expression of a diverse group of genes that contribute to increasing oxygen delivery and metabolic accommodation to hypoxia.

There have been several attempts to therapeutically target HIF-1 through the blockade of its interaction with HIF-1β, interfering with its DNA binding affinity, disruption of its transcriptional activity, and inhibiting its mRNA and protein expression. Till now, development of therapies targeting HIF-1 remains hindered. Therefore, it is imperative to explore the mechanism of HIF-1 regulation in cancer cells and investigate new possibilities to therapeutically target HIF-1 signaling.

it is imperative to explore the mechanism of HIF-1 regulation in cancer cells and investigate new possibilities to therapeutically target HIF-1 signaling

Previously these authors have described a non-canonical stabilization of HIF-1 by CDK1 in a VHL-independent manner, and further proposed CDK4 also as a HIF-1 stabilizer. The complex then translocates into the nucleus, interacts with other co-factors, binds target genes, and activates or represses transcription. In the nucleus, Smurf2 interacts with SMAD7 and translocates to the cytoplasm, where it targets the TGF-β receptor as well as SMAD2 and SMAD3 for ubiquitination and degradation.

Other examples of Smurf2 substrates include HSP27, Yin Yang 1, Krüppel-like factor 5, and poly polymerase-1.

The El-Deiry Research Team concluded in their Oncotarget Research Output, "we propose a non-canonical mechanism involving Smurf2 in HIF-1α degradation upon CDK4/6 inhibitor treatment, which provides novel insights in HIF-1α regulation. It sheds light on the HIF-1α stabilization in cancer as well as suggests new possibilities of therapeutic angiogenesis."

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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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