Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis

Cell Rep. 2021 Oct 19;37(3):109870. doi: 10.1016/j.celrep.2021.109870.

Abstract

FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1FBXO31 promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and -2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer.

Keywords: AKT; BCI; CRL; DUSP6; ERK; F-box protein; FBXO31; prostate cancer; ubiquitin; ubiquitin ligases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • Cyclohexylamines / pharmacology
  • Dual Specificity Phosphatase 6 / antagonists & inhibitors
  • Dual Specificity Phosphatase 6 / genetics
  • Dual Specificity Phosphatase 6 / metabolism*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Enzyme Stability
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Indenes / pharmacology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • 2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one
  • Antineoplastic Agents
  • Cullin Proteins
  • Cyclohexylamines
  • Enzyme Inhibitors
  • F-Box Proteins
  • FBXO31 protein, human
  • Indenes
  • Tumor Suppressor Proteins
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6