bims-nurfca 2023-08-20 papers

Issue of 2023–08–20
three papers selected by
Caner Geyik, Istinye University

Redox Biol. 2023 Aug 09. pii: S2213-2317(23)00240-9. [Epub ahead of print]65 102839

The NRF2-p97-NRF2 negative feedback loop.

Aryatara Shakya, Pengfei Liu, Jack Godek, Nicholas W McKee, Matthew Dodson, Annadurai Anandhan, Aikseng Ooi, Joe G N Garcia, Max Costa, Eli Chapman, Donna D Zhang.

p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis. Using CRISPR/Cas9 genome editing, we generated endogenous p97 ARE-mutated BEAS-2B cell lines. These p97 ARE-mutated cell lines exhibit altered expression of p97 and NRF2, as well as a compromised response to NRF2 inducers. Importantly, we also found a positive correlation between NRF2 activation and p97 expression in human cancer patients. Finally, using chronic arsenic-transformed cell lines, we demonstrated a synergistic effect of NRF2 and p97 inhibition in killing cancer cells with high NRF2 and p97 expression. Our study suggests dual upregulation of NRF2 and p97 occurs in certain types of cancers, suggesting that inhibition of both NRF2 and p97 could be a promising treatment strategy for stratified cancer patients.

Keywords: Arsenic; Cancer; Nrf2; Oxidative stress; Proteostasis; p97

DOI: https://doi.org/10.1016/j.redox.2023.102839

Oncogene. 2023 Aug 12.

NRF2 has a splicing regulatory function involving the survival of motor neuron (SMN) in non-small cell lung cancer.

Qinqin Cui, Wei Wang, Akhileshwar Namani, Hongyan Wang, Ahmed Hammad, Pu Huang, Yang Gao, Mohamed Elshaer, Yihe Wu, Xiu Jun Wang, Xiuwen Tang.

The nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) signaling pathway is frequently deregulated in human cancers. The critical functions of NRF2, other than its transcriptional activation, in cancers remain largely unknown. Here, we uncovered a previously unrecognized role of NRF2 in the regulation of RNA splicing. Global splicing analysis revealed that NRF2 knockdown in non-small cell lung cancer (NSCLC) A549 cells altered 839 alternative splicing (AS) events in 485 genes. Mechanistic studies demonstrated that NRF2 transcriptionally regulated SMN mRNA expression by binding to two antioxidant response elements in the SMN1 promoter. Post-transcriptionally, NRF2 was physically associated with the SMN protein. The Neh2 domain of NRF2, as well as the YG box and the region encoded by exon 7 of SMN, were required for their interaction. NRF2 formed a complex with SMN and Gemin2 in nuclear gems and Cajal bodies. Furthermore, the NRF2-SMN interaction regulated RNA splicing by expressing SMN in NRF2-knockout HeLa cells, reverting some of the altered RNA splicing. Moreover, SMN overexpression was significantly associated with alterations in the NRF2 pathway in patients with lung squamous cell carcinoma from The Cancer Genome Atlas. Taken together, our findings suggest a novel therapeutic strategy for cancers involving an aberrant NRF2 pathway.

DOI: https://doi.org/10.1038/s41388-023-02799-z

Inflamm Regen. 2023 Aug 18. 43(1): 42

Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery.

Kenly Wuputra, Ming-Ho Tsai, Kohsuke Kato, Chia-Chen Ku, Jia-Bin Pan, Ya-Han Yang, Shigeo Saito, Chun-Chieh Wu, Ying-Chu Lin, Kuang-Hung Cheng, Kung-Kai Kuo, Michiya Noguchi, Yukio Nakamura, Tohru Yoshioka, Deng-Chyang Wu, Chang-Shen Lin, Kazunari K Yokoyama.

BACKGROUND: Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the "AhR-Nrf2 gene battery", which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood.
METHODS: Knockdown and forced expression of AhR-Nrf2 battery members were used to examine the molecular interactions between the AhR-Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR-Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR-Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors.
RESULTS: Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR-Jdp2-Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells.
CONCLUSIONS: Jdp2 plays a critical role in AhR promoter activation through the AhR-Jdp2-Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras-Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.

Keywords: Antioxidation; Aryl hydrocarbon receptor; Dioxin responsive element; Jun dimerization protein 2; Nuclear factor (erythroid-derived 2)-like 2 transcription factor; Oxidative stress; Reactive oxygen species; Transcriptional regulation

DOI: https://doi.org/10.1186/s41232-023-00290-6