Thus, our present study sheds light on the impact of 20S proteasome regulation and function on cancer cells and provides crucial insights into three related issues, (i) the inactivation of the tumor suppressors p53 and Rb in cancer cells, (ii) cross talk of NRF3 with the homologs NRF1 and NRF2, and (iii) the development of anticancer drugs, as discussed in more detail below. This evidence concerns the gene NFE2L3 and cancer.