Abstract
Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial for cancer cell growth. However, the mechanism of how proteasome activity is maintained in cancer cells has remained unclear. The CNC family transcription factor NFE2L1 induces the expression of almost all proteasome-related genes under proteasome inhibition. Both NFE2L1 and its phylogenetically closest homolog, NFE2L3, are highly expressed in several types of cancer, such as colorectal cancer. Here, we demonstrate that NFE2L1 and NFE2L3 complementarily maintain basal proteasome activity in cancer cells. Double knockdown of NFE2L1 and NFE2L3 impaired basal proteasome activity in cancer cells and cancer cell resistance to a proteasome inhibitor anticancer drug, bortezomib, by significantly reducing the basal expression of seven proteasome-related genes: PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, and POMP Interestingly, the molecular basis behind these cellular consequences was that NFE2L3 repressed NFE2L1 translation by the induction of the gene encoding the translational regulator CPEB3, which binds to the NFE2L1 3' untranslated region and decreases polysome formation on NFE2L1 mRNA. Consistent results were obtained from clinical analysis, wherein patients with cancer having tumors expressing higher levels of CPEB3/NFE2L3 exhibit poor prognosis. These results provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NFE2L3-CPEB3-NFE2L1 translational repression axis.
Highlights
Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial for cancer cell growth
We found that the double knockdown of NFE2L1 and NFE2L3 significantly decreased basal proteasome activity in living cancer cells (Fig. 1A)
Using reverse transcription-quantitative PCR (RT-qPCR), we showed that the mRNA levels of PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, and POMP were significantly decreased by the double knockdown of NFE2L1 and NFE2L3 (Fig. 1C)
Summary
Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial for cancer cell growth. Consistent results were obtained from clinical analysis, wherein patients with cancer having tumors expressing higher levels of CPEB3/NFE2L3 exhibit poor prognosis These results provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NFE2L3-CPEB3-NFE2L1 translational repression axis. Gene Expression Profiling Interactive Analysis (GEPIA) Web server [10], the NFE2L3 gene is shown to be highly expressed in many types of tumors, such as testicular germ cell tumors, pancreatic adenocarcinoma, colon adenocarcinoma (COAD), and rectal adenocarcinoma (READ), whereas the NFE2L1 gene is highly expressed in almost all types of normal and tumor tissue These insights imply the functional correlation between NFE2L1 and NFE2L3 with respect to the maintenance of basal proteasome activity in cancer cells. We demonstrate the novel regulatory mechanism of basal proteasome activity in cancer cells where NFE2L1 and NFE2L3 complementarily, but not simultaneously, maintain the basal expression of proteasome-related genes through CPEB3-mediated translational repression
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