Inhibition of USP2 Enhances TRAIL-Mediated Cancer Cell Death through Downregulation of Survivin

Ubiquitin-specific protease 2 (USP2) is a deubiquitinase belonging to the USPs subfamily. USP2 has been known to display various biological effects including tumorigenesis and inflammation. Therefore, we aimed to examine the sensitization effect of USP2 in TRAIL-mediated apoptosis. The pharmacological inhibitor (ML364) and siRNA targeting USP2 enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cancer cell death, but not normal cells. Mechanistically, USP2 interacted with survivin, and ML364 degraded survivin protein expression by increasing the ubiquitination of survivin. Overexpression of survivin or USP2 significantly prevented apoptosis through cotreatment with ML364 and TRAIL, whereas a knockdown of USP2 increased sensitivity to TRAIL. Taken together, our data suggested that ML364 ubiquitylates and degrades survivin, thereby increasing the reactivity to TRAIL-mediated apoptosis in cancer cells.

[1]  Xia Li,et al.  ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system , 2022, Frontiers in Microbiology.

[2]  S. Woo,et al.  Inhibition of USP1 enhances anticancer drugs-induced cancer cell death through downregulation of survivin and miR-216a-5p-mediated upregulation of DR5 , 2022, Cell Death & Disease.

[3]  S. Ramakrishna,et al.  Dual role of deubiquitinating enzyme USP19 regulates mitotic progression and tumorigenesis by stabilizing survivin. , 2022, Molecular therapy : the journal of the American Society of Gene Therapy.

[4]  W. Wang,et al.  Regulation of survivin protein stability by USP35 is evolutionarily conserved. , 2021, Biochemical and biophysical research communications.

[5]  H. Kitamura,et al.  USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes , 2021, International journal of molecular sciences.

[6]  S. Woo,et al.  Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization , 2019, Redox biology.

[7]  S. Woo,et al.  Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation , 2019, Biomolecules.

[8]  U. Knippschild,et al.  TRAILblazing Strategies for Cancer Treatment , 2019, Cancers.

[9]  Li Ma,et al.  Ubiquitin-specific peptidase 2a (USP2a) deubiquitinates and stabilizes β-catenin. , 2018, American journal of cancer research.

[10]  S. Woo,et al.  Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress , 2018, Experimental & Molecular Medicine.

[11]  Yujie Ren,et al.  USP2a Supports Metastasis by Tuning TGF-β Signaling. , 2018, Cell reports.

[12]  S. Woo,et al.  BIX-01294 sensitizes renal cancer Caki cells to TRAIL-induced apoptosis through downregulation of survivin expression and upregulation of DR5 expression , 2018, Cell Death Discovery.

[13]  Y. Chun,et al.  CYP1B1 Activates Wnt/β-Catenin Signaling through Suppression of Herc5-Mediated ISGylation for Protein Degradation on β-Catenin in HeLa Cells , 2017, Toxicological research.

[14]  Charles Swanton,et al.  Renal cell carcinoma , 2017, Nature Reviews Disease Primers.

[15]  C. Porta,et al.  Choosing the right cell line for renal cell cancer research , 2016, Molecular Cancer.

[16]  Jennifer T. Fox,et al.  Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models* , 2016, The Journal of Biological Chemistry.

[17]  P. Goudarzi,et al.  Overexpression of ubiquitin-specific protease 2a (USP2a) and nuclear factor erythroid 2-related factor 2 (Nrf2) in human gliomas , 2016, Journal of the Neurological Sciences.

[18]  A. Anel,et al.  Onto better TRAILs for cancer treatment , 2016, Cell Death and Differentiation.

[19]  Anup Shrestha,et al.  Ubiquitin specific protease 2 acts as a key modulator for the regulation of cell cycle by adiponectin and leptin in cancer cells , 2015, Molecular and Cellular Endocrinology.

[20]  M. Freeman,et al.  Assess the expression of ubiquitin specific protease USP2a for bladder cancer diagnosis , 2015, BMC Urology.

[21]  Bill B. Chen,et al.  The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin* , 2015, The Journal of Biological Chemistry.

[22]  Y. Xiong,et al.  CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity. , 2014, Molecular cell.

[23]  Hai-bo Xiao,et al.  The role of the ubiquitin-proteasome pathway in cancer development and treatment. , 2014, Frontiers in bioscience.

[24]  R. Motzer,et al.  Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. , 2014, The New England journal of medicine.

[25]  M. Loda,et al.  USP2a alters chemotherapeutic response by modulating redox , 2013, Cell Death and Disease.

[26]  Li-jun Hou,et al.  Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade , 2013, Journal of Clinical Neuroscience.

[27]  Eric F. Johnson,et al.  Ubiquitin-specific Cysteine Protease 2a (USP2a) Regulates the Stability of Aurora-A , 2011, The Journal of Biological Chemistry.

[28]  D. Calvisi,et al.  Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. , 2011, Gastroenterology.

[29]  D. Lane,et al.  MdmX is a substrate for the deubiquitinating enzyme USP2a , 2010, Oncogene.

[30]  David Komander,et al.  Breaking the chains: structure and function of the deubiquitinases , 2009, Nature Reviews Molecular Cell Biology.

[31]  R. Deshaies,et al.  RING domain E3 ubiquitin ligases. , 2009, Annual review of biochemistry.

[32]  Keith D Wilkinson,et al.  Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. , 2009, Annual review of biochemistry.

[33]  G. Tiegs,et al.  Down-regulation of the De-ubiquitinating Enzyme Ubiquitin-specific Protease 2 Contributes to Tumor Necrosis Factor-α-induced Hepatocyte Survival* , 2009, Journal of Biological Chemistry.

[34]  Tommer Ravid,et al.  Diversity of degradation signals in the ubiquitin–proteasome system , 2008, Nature Reviews Molecular Cell Biology.

[35]  R. Korneluk,et al.  Degradation of Survivin by the X-linked Inhibitor of Apoptosis (XIAP)-XAF1 Complex* , 2007, Journal of Biological Chemistry.

[36]  M. Saville,et al.  The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2 , 2007, The EMBO journal.

[37]  M. Loda,et al.  The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. , 2004, Cancer cell.

[38]  S. H. Baek,et al.  Molecular Cloning of a Novel Ubiquitin-specific Protease, UBP41, with Isopeptidase Activity in Chick Skeletal Muscle* , 1997, The Journal of Biological Chemistry.