FBXO22, an epigenetic multiplayer coordinating senescence, hormone signaling, and metastasis

Cancer Sci. 2020 Aug;111(8):2718-2725. doi: 10.1111/cas.14534. Epub 2020 Jul 17.


Ubiquitin-dependent protein degradation has been implicated in the control of various cellular processes such as cell cycle control, transcriptional regulation, DNA damage repair, and apoptosis, many of which are involved in the initiation, progression, metastasis, and drug resistance of cancers. E3 ubiquitin ligases are known to be the second most prevalent cancer-related functional gene family next to protein kinases. Of these, FBXO22, an F-box receptor subunit of SCF E3 ligase, has recently been proposed to play a critical role in multiple aspects related to cancer development and therapy response. Firstly, FBXO22 is a key regulator of senescence induction through ubiquitylation of p53 for degradation. FBXO22 also acts as a molecular switch for the antagonistic and agonistic actions of selective estrogen receptor modulators (SERM) and determines the sensitivity of breast cancer to SERM by ubiquitylating KDM4B complexed with unliganded or SERMs-bound estrogen receptor (ER). Furthermore, FBXO22 binds to Bach1, a pro-metastatic transcription factor, suppressing Bach1-driven metastasis of lung adenocarcinoma, and loss of FBXO22 facilitates metastasis. These findings, as well as other reports, unveiled strikingly important roles of FBXO22 in cancer development and therapeutic strategy. In this review, we summarize recent findings of how FBXO22 regulates major cancer suppression pathways.

Keywords: Bach1; F-box protein; KDM4; p53; ubiquitin.

Publication types

  • Review

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Movement / genetics
  • Cellular Senescence / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Epigenesis, Genetic*
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Protein Subunits / metabolism
  • Proteolysis
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Estrogen / metabolism
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Selective Estrogen Receptor Modulators / metabolism
  • Signal Transduction / genetics
  • Ubiquitination


  • F-Box Proteins
  • FBXO22 protein, human
  • Fbxo22 protein, mouse
  • Protein Subunits
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators
  • SKP Cullin F-Box Protein Ligases