Oncotarget

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

Shuai Zhao and Wafik S. El-Deiry _

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Oncotarget. 2021; 12:1970-1979. https://doi.org/10.18632/oncotarget.28081

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Abstract

Shuai Zhao1,2,4,5 and Wafik S. El-Deiry1,2,3,4,5,6

1 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA

2 Pathobiology Graduate Program, Brown University, Providence, RI, USA

3 Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA

4 Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI, USA

5 Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI, USA

6 Hematology/Oncology Division, Lifespan Cancer Institute, Providence, RI, USA

Correspondence to:

Wafik S. El-Deiry, email: wafik@brown.edu

Keywords: Smurf2; CDK4/6 inhibition; HIF1alpha; hypoxia; cancer therapy

Received: September 03, 2021     Accepted: September 09, 2021     Published: September 28, 2021

Copyright: © 2021 Zhao and El-Deiry. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

The major adaptive response to hypoxia involves hypoxia-inducible factor HIF-1α which is regulated by von Hippel Lindau (VHL) E3 ligase. We previously observed a stabilization of HIF-1α by cyclin-dependent kinases CDK1 and CDK4/6 that is independent of VHL, hypoxia or p53, and found that CDK4/6 inhibitors destabilize HIF-1α under normoxia and hypoxia. To further investigate the molecular mechanism of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors, we performed a proteomic screen on immunoprecipitated HIF-1α from hypoxic colorectal cancer cells that were either untreated or treated with CDK1 inhibitor Ro3306 and CDK4/6 inhibitor palbociclib. Our proteomics screen identified a number of candidates that were enriched in palbociclib-treated hypoxic cells including SMAD specific E3 ubiquitin protein ligase 2 (Smurf2). We also identified a HIF-1α peptide that appeared to be differentially phosphorylated after palbociclib treatment. Gene knockdown of SMURF2 increased basal expression of HIF-1α even in the presence of Ro3306 or two different CDK4/6 inhibitors, palbociclib and abemaciclib. Overexpression of Smurf2 inhibited expression of HIF-1α and enhanced HIF-1α ubiquitination in normoxia. Proteasome inhibitor MG-132 partially rescued HIF-1α expression when Smurf2 was overexpressed. Smurf2 overexpression also inhibited HIF-1α 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. Our results unravel a previously unknown mechanism involving Smurf2 for HIF-1α destabilization in CDK4/6 inhibitor-treated cells, thereby shedding light on VHL-independent HIF-1α regulation.


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