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.

中文翻译：

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NFE2L1和NFE2L3通过CPEB3介导的翻译抑制来互补地维持癌细胞中的基础蛋白酶体活性。

蛋白酶体是细胞稳态必需的蛋白酶复合物，它们的活性对于癌细胞的生长至关重要。然而，如何在癌细胞中维持蛋白酶体活性的机制仍不清楚。CNC家族转录因子NFE2L1在蛋白酶体抑制下诱导几乎所有蛋白酶体相关基因的表达。NFE2L1及其系统发育上最接近的同源物NFE2L3在多种类型的癌症（例如结直肠癌）中都高度表达。在这里，我们证明NFE2L1和NFE2L3互补地维持癌细胞中的基础蛋白酶体活性。NFE2L1和NFE2L3的双重敲低会损害癌细胞中的基础蛋白酶体活性以及癌细胞对蛋白酶体抑制剂抗癌药硼替佐米的耐药性，通过显着降低7个蛋白酶体相关基因的基础表达：PSMB3，PSMB7，PSMC2，PSMD3，PSMG2，PSMG3和POMP有趣的是，这些细胞后果的分子基础是NFE2L3通过诱导编码该基因的基因来抑制NFE2L1翻译。翻译调节剂CPEB3，其与NFE2L1 3'非翻译区结合并减少NFE2L1 mRNA上的多核糖体形成。从临床分析中获得一致的结果，其中患有肿瘤的患者表达更高水平的CPEB3 / NFE2L3的癌症患者预后较差。这些结果通过NFE2L3-CPEB3-NFE2L1平移抑制轴提供了癌细胞中蛋白酶体基础活性的新调节机制。这些细胞后果的分子基础是NFE2L3通过诱导编码翻译调节子CPEB3的基因来抑制NFE2L1翻译，该基因与NFE2L1 3'非翻译区结合并减少NFE2L1 mRNA上多核小体的形成。从临床分析中获得一致的结果，其中患有肿瘤的患者表达更高水平的CPEB3 / NFE2L3的癌症患者预后较差。这些结果通过NFE2L3-CPEB3-NFE2L1平移抑制轴提供了癌细胞中蛋白酶体基础活性的新调节机制。这些细胞后果的分子基础是NFE2L3通过诱导编码翻译调节子CPEB3的基因来抑制NFE2L1翻译，该基因与NFE2L1 3'非翻译区结合并减少NFE2L1 mRNA上多核小体的形成。从临床分析中获得一致的结果，其中患有肿瘤的患者表达更高水平的CPEB3 / NFE2L3的癌症患者预后较差。这些结果通过NFE2L3-CPEB3-NFE2L1平移抑制轴提供了癌细胞中蛋白酶体基础活性的新调节机制。从临床分析中获得一致的结果，其中患有肿瘤的患者表达更高水平的CPEB3 / NFE2L3的癌症患者预后较差。这些结果通过NFE2L3-CPEB3-NFE2L1平移抑制轴提供了癌细胞中蛋白酶体基础活性的新调节机制。从临床分析中获得一致的结果，其中患有肿瘤的患者表达更高水平的CPEB3 / NFE2L3的癌症患者预后较差。这些结果通过NFE2L3-CPEB3-NFE2L1平移抑制轴提供了癌细胞中蛋白酶体基础活性的新调节机制。