The transcription factor BACH1 at the crossroads of cancer biology: From epithelial-mesenchymal transition to ferroptosis.

The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap'n'collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their genetic targets remains incompletely defined. Here we use RNA-sequencing-based transcriptional profiling and quantitative proteomics to delineate the overlapping and differential genetic programs effected by the three NRF transcription factors. We then create consensus target gene sets regulated by NRF1, NRF2, and NRF3 and define the integrity of these gene sets for probing NRF activity in mammalian cell culture and human tissues. Together, our data provide a quantitative assessment of how NRF family members sculpt proteomes and transcriptomes, providing a framework to understand the critical physiological importance of NRF transcription factors and to establish pharmacologic approaches for therapeutically activating these transcriptional programs in disease.

https://www.mdpi.com/2076-3921/9/10/1025/pdf

Defining the Functional Targets of Cap'n'collar Transcription Factors NRF1, NRF2, and NRF3.

The physiological roles of the NRF2-related transcription factor NRF3 (NFE2L3) have remained unknown for decades. The remarkable development of human cancer genome databases has led to strong suggestions that NRF3 has functional significance in cancer; specifically, high NRF3 mRNA levels are induced in many cancer types, such as colorectal cancer and pancreatic adenocarcinoma, and are associated with poor prognosis. On the basis of this information, the involvement of NRF3 in tumorigenesis and cancer malignancy has been recently proposed. NRF3 confers cancer cells with selective growth advantages by enhancing 20S proteasome assembly through induction of the chaperone gene proteasome maturation protein (POMP) and consequently promoting degradation of the tumor suppressors p53 and retinoblastoma (Rb) in a ubiquitin-independent manner. This new finding offers insight into the proteasomal but not the genetic inactivation mechanism of tumor suppressors. Moreover, NRF3 promotes cancer malignancy-related processes, including metastasis and angiogenesis. Finally, the molecular mechanisms underlying NRF3 activation have been elucidated, and this knowledge is expected to provide many insights that are useful for the development of anticancer drugs that attenuate NRF3 transcriptional activity. Collectively, the evidence indicates that NRF3 confers cells with six so-called “hallmarks of cancer”, implying that it exhibits cancer driver gene-like function. This review describes recent research advances regarding the newly discovered addiction of cancer cells to NRF3 compared to NRF2.

https://www.mdpi.com/2072-6694/12/9/2681/pdf

Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors

NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway with cholesterol uptake and lipogenesis inhibition.

Trash Talk: Mammalian Proteasome Regulation at the Transcriptional Level.

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.

NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression.

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 NRF1 induces the expression of almost all proteasome-related genes under proteasome inhibition. NRF1 and its phylogenetically closest homolog NRF3 are both highly expressed in several types of cancers, such as colorectal cancer. Herein, we demonstrate that NRF1 and NRF3 complementarily maintain basal proteasome activity in cancer cells. A double knockdown of NRF1 and NRF3 impaired the basal proteasome activity in cancer cells and the cancer cell resistance to a proteasome inhibitor anticancer drug bortezomib by significantly reducing basal expression of seven proteasome-related genes, including PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, and POMP. Interestingly, the molecular basis behind these cellular consequences was that NRF3 repressed NRF1 translation by the gene induction of translational regulator CPEB3, which binds to NRF1-39UTR and decreases polysome formation on NRF1 mRNA. Consistent results were obtained from clinical analysis, wherein patients with cancer having higher CPEB3/NRF3-expressing tumors exhibit poor prognosis. These results provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NRF3-CPEB3-NRF1 translational repression axis.

https://www.biorxiv.org/content/biorxiv/early/2020/01/11/2020.01.10.902718.full.pdf

Miyako Hiraoka

Papers

NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression.

NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression