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."
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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