Smurf2 Regulation of HIF-1α in Cancer Cells



September 29, 2021

Oncotarget’s cover paper this week (Volume 12, Issue 20) is entitled, "Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase," by researchers from the Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI; Pathobiology Graduate Program, Brown University, Providence, RI; Department of Pathology and Laboratory Medicine, Brown University, Providence, RI; Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute, Providence, RI; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI; Hematology/Oncology Division, Lifespan Cancer Institute, Providence, RI. 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. Sign up for free Altmetric alerts about this article - DOI - Full text - Correspondence to - Wafik S. El-Deiry - Keywords - Smurf2, CDK4/6 inhibition, HIF1alpha, hypoxia, cancer therapy About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit or connect with: SoundCloud - Facebook - Twitter - YouTube - LinkedIn - Pinterest - Reddit - Oncotarget is published by Impact Journals, LLC please visit or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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