F-Box Protein 11 Suppresses Cell Proliferation and Aerobic Glycolysis in Glioblastomas by Mediating the Ubiquitin Degradation of Cdc25A.

Glioblastoma is a malignant CNS tumor with an extremely poor prognosis. F-box protein 11 (FBXO11) has E3 ubiquitin ligase activity and participates in the pathogenesis of multiple tumors but the role and mechanism of FBXO11 activity in glioblastoma remain unknown. In this study, FBXO11 was first observed to be downregulated in glioblastoma tissues and cell lines. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) and colony formation assays and enzyme linked immunosorbent assay (ELISA) demonstrated that overexpression of FBXO11 suppressed proliferation and aerobic glycolysis and induced cell cycle arrest in U251-MG and A172 cells. FBXO1 decreased cell division cycle 25 A (Cdc25A) expression through ubiquitin degradation in a coprecipitation assay. A Western blot assay validated FBXO11 suppression of PKM2 dephosphorylation and c-Myc-mediated aerobic glycolysis via reduction of Cdc25A. In addition, a rescue experiment revealed that FBXO11 suppressed proliferation and aerobic glycolysis, both of which were reversed by overexpression of Cdc25A. FBXO11 overexpression also inhibited tumorigenesis via suppressing Cdc25A expression in vivo. These findings indicate that FBXO11 suppresses cell proliferation and aerobic glycolysis in glioblastomas by mediating the ubiquitin degradation of Cdc25A thereby providing insight into mechanisms of glioblastoma tumorigenesis and identifying a new potential therapeutic strategy.

[1]  Yiwei Liao,et al.  ANXA2P2/miR-9/LDHA axis regulates Warburg effect and affects glioblastoma proliferation and apoptosis. , 2020, Cellular signalling.

[2]  Yuan Fang,et al.  CD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis , 2019, Nature Communications.

[3]  Anindya Dutta,et al.  Regulation of TGF-β signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2 , 2013, Cell cycle.

[4]  K. Basler,et al.  β-Catenin hits chromatin: regulation of Wnt target gene activation , 2009, Nature Reviews Molecular Cell Biology.

[5]  Zhixian Jiang,et al.  SNHG9/miR-199a-5p/Wnt2 Axis Regulates Cell Growth and Aerobic Glycolysis in Glioblastoma. , 2019, Journal of neuropathology and experimental neurology.

[6]  J. Ai,et al.  miR-143 inhibits glycolysis and depletes stemness of glioblastoma stem-like cells. , 2013, Cancer letters.

[7]  Xin Hu,et al.  FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development. , 2015, Cancer letters.

[8]  Gianluca Bontempi,et al.  TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data , 2015, Nucleic acids research.

[9]  D. Khosla,et al.  Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. , 2016, Annals of translational medicine.

[10]  Qi Yao,et al.  The F‐box protein FBXO11 restrains hepatocellular carcinoma stemness via promotion of ubiquitin‐mediated degradation of Snail , 2020, FEBS open bio.

[11]  Konrad Basler,et al.  The many faces and functions of β‐catenin , 2012, The EMBO journal.

[12]  Qian Sun,et al.  BMP4 inhibits glioblastoma invasion by promoting E-cadherin and claudin expression. , 2019, Frontiers in bioscience.

[13]  S. Huber,et al.  Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma , 2017, Cellular Physiology and Biochemistry.

[14]  L. Pfeffer,et al.  The Oncogenic MicroRNA-21 Inhibits the Tumor Suppressive Activity of FBXO11 to Promote Tumorigenesis* , 2015, The Journal of Biological Chemistry.

[15]  W. Gu,et al.  FBXO11 Promotes the Neddylation of p53 and Inhibits Its Transcriptional Activity* , 2007, Journal of Biological Chemistry.

[16]  A. Rust,et al.  Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma , 2012, Proceedings of the National Academy of Sciences.

[17]  M. V. Vander Heiden,et al.  Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. , 2011, Annual review of cell and developmental biology.

[18]  S. Kim,et al.  FBXO11 represses cellular response to hypoxia by destabilizing hypoxia-inducible factor-1α mRNA. , 2015, Biochemical and biophysical research communications.

[19]  K. Helin,et al.  Aggressiveness of non-EMT breast cancer cells relies on FBXO11 activity , 2018, Molecular Cancer.

[20]  M. Weller,et al.  Chapter 23 - Glioblastoma , 2016 .

[21]  C. Dang,et al.  Deregulation of Glucose Transporter 1 and Glycolytic Gene Expression by c-Myc* , 2000, The Journal of Biological Chemistry.

[22]  Weiwei Yang,et al.  PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis , 2016, Nature Communications.

[23]  G. Semenza,et al.  Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression , 2010, Proceedings of the National Academy of Sciences.

[24]  Q. Pang,et al.  NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma , 2021, BMC Cancer.

[25]  Michele Pagano,et al.  FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas , 2012, Nature.

[26]  C. Stournaras,et al.  The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells , 2016, Cellular Physiology and Biochemistry.

[27]  Qifu Li,et al.  miR-181a-5p inhibits the proliferation and invasion of drug-resistant glioblastoma cells by targeting F-box protein 11 expression , 2020, Oncology letters.

[28]  J. Rudolph.  Inhibiting transient protein–protein interactions: lessons from the Cdc25 protein tyrosine phosphatases , 2007, Nature Reviews Cancer.

[29]  Lai-jun Song,et al.  HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway , 2017, Front. Cell. Neurosci..

[30]  Michael Schieber,et al.  FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome , 2020, Blood Cancer Journal.

[31]  P. Li,et al.  The tumor suppressive miR-26a regulation of FBXO11 inhibits proliferation, migration and invasion of hepatocellular carcinoma cells. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[32]  Fan Zhang,et al.  LINC01436, regulating miR‐585 and FBXO11, is an oncogenic lncRNA in the progression of gastric cancer , 2019, Cell biology international.