NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression
NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression
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DOI：
10.1128/mcb.00010-20
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发表时间：
2020-07-01
影响因子：
5.3
通讯作者：
Kobayashi, Akira
中科院分区：
文献类型：
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作者：
Waku, Tsuyoshi;Katayama, Hiroyuki;Kobayashi, Akira
蛋白酶体是细胞内稳态所必需的蛋白酶复合物，其活性对癌细胞生长至关重要。然而，蛋白酶体活性如何在癌细胞中维持的机制仍不清楚。CNC家族转录因子NFE 2L 1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。NFE 2L 1及其在遗传学上最接近的同源物NFE 2L 3在几种类型的癌症中高度表达，例如结肠直肠癌。在这里，我们证明了NFE 2L 1和NFE 2L 3互补地维持癌细胞中的基础蛋白酶体活性。NFE 2L 1和NFE 2L 3的双敲低通过显著降低七种蛋白酶体相关基因的基础表达来损害癌细胞中的基础蛋白酶体活性和癌细胞对蛋白酶体抑制剂抗癌药物硼替佐米的抗性：PSMB 3、PSMB 7、PSMC 2、PSMD 3、PSMG 2、PSMG 3和POMP。有趣的是，这些细胞结果背后的分子基础是NFE 2L 3通过诱导编码翻译调节因子CPEB 3的基因来抑制NFE 2L 1翻译，该基因结合NFE 2L 1 3 =非翻译区并减少NFE 2L 1 mRNA上的多核糖体形成。从临床分析中获得了一致的结果，其中具有表达较高水平的CPEB 3/NFE 2L 3的肿瘤的癌症患者表现出不良预后。这些结果提供了通过NFE 2L 3-CPEB 3-NFE 2L 1翻译抑制轴在癌细胞中基础蛋白酶体活性的新的调节机制。
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 = un-translated region and decreases polysome formation on NFE2L1 mRNA. Consistent results were obtained from clinical analysis, wherein patients with cancer having tu-mors 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.