Send to

Choose Destination
Cancer Sci. 2019 Nov 19. doi: 10.1111/cas.14244. [Epub ahead of print]

New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis via the 20S proteasome.

Author information

Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, 610-0394, Japan.
Department of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, 610-0394, Japan.


Accumulating evidence has revealed that human cancers develop by sequentially mutating pivotal genes, including driver genes, and acquiring cancer hallmarks. For instance, cancer cells are addicted to the transcription factor NRF2 (NFE2L2), which is a driver gene and that utilizes the cellular cytoprotection system against oxidative stress and metabolic pathway reprogramming for sustaining high growth. Our group has recently discovered new addiction to the NRF2-related factor NRF3 (NFE2L3) in cancer. For many years, the physiological function of NRF3 remained obscure, in part because Nrf3-deficient mice do not exhibit apparent abnormalities. Nevertheless, human cancer genome databases suggest critical roles of NRF3 in cancer because of high NRF3 mRNA induction in several cancer types, such as colorectal cancer and pancreatic adenocarcinoma, with a poor prognosis. We found that NRF3 promotes tumor growth and malignancy by activating ubiquitin-independent 20S proteasome assembly through inducing the expression of the POMP chaperone and thereby degrading the tumor suppressors p53 and Rb. The NRF3-POMP-20S proteasome axis has an entirely different effect on cancer than NRF2. In this review, we describe recent research advances regarding the new cancer effector NRF3, including unclarified ubiquitin-independent proteolysis by the NRF3-POMP-20S proteasome axis. The expected development of cancer therapeutic interventions for this axis is also discussed.


20S proteasome; NRF2; NRF3; p53; ubiquitin-independent degradation

Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center