NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein

Mol Cell Biol. 2020 Apr 28;40(10):e00597-19. doi: 10.1128/MCB.00597-19. Print 2020 Apr 28.


Proteasomes are essential protease complexes that maintain cellular homeostasis, and aberrant proteasomal activity supports cancer development. The regulatory mechanisms and biological function of the ubiquitin-26S proteasome have been studied extensively, while those of the ubiquitin-independent 20S proteasome system remain obscure. Here, we show that the cap 'n' collar (CNC) family transcription factor NRF3 specifically enhances 20S proteasome assembly in cancer cells and that 20S proteasomes contribute to colorectal cancer development through ubiquitin-independent proteolysis of the tumor suppressor p53 and retinoblastoma (Rb) proteins. The NRF3 gene is highly expressed in many cancer tissues and cell lines and is important for cancer cell growth. In cancer cells, NRF3 upregulates the assembly of the 20S proteasome by directly inducing the gene expression of the 20S proteasome maturation protein POMP. Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increases p53 activities for tumor suppression, including cell cycle arrest and induction of apoptosis. Furthermore, protein stability and cell viability assays using two distinct proteasome inhibitor anticancer drugs, the 20S proteasome inhibitor bortezomib and the ubiquitin-activating enzyme E1 inhibitor TAK-243, show that the upregulation of the NRF3-POMP axis leads to ubiquitin-independent proteolysis of p53 and Rb and to impaired sensitivity to bortezomib but not TAK-243. More importantly, the NRF3-POMP axis supports tumorigenesis and metastasis, with higher NRF3/POMP expression levels correlating with poor prognoses in patients with colorectal or rectal adenocarcinoma. These results suggest that the NRF3-POMP-20S proteasome assembly axis is significant for cancer development via ubiquitin-independent proteolysis of tumor suppressor proteins.

Keywords: 20S proteasome assembly; NFE2L3; NRF3; POMP; Rb; TP53; cancer development; colorectal cancer; p53; retinoblastoma; ubiquitin-independent proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Molecular Chaperones / metabolism*
  • Neoplasms / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis
  • Retinoblastoma Protein / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / metabolism


  • Basic-Leucine Zipper Transcription Factors
  • Molecular Chaperones
  • NFE2L3 protein, human
  • Retinoblastoma Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • proteasome maturation protein
  • Proteasome Endopeptidase Complex