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EMSY stabilization in KEAP1-mutant lung cancer disrupts genome stability and type I interferon signaling

Cell Death & Differentiation volume 30, pages 1397–1399 (2023)Cite this article

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Perturbed proteostasis is an emerging hallmark of cancer, exhibiting aberrations in protein degradation by the ubiquitin-proteasome system (UPS) [1,2,3]. Numerous studies provide evidence that dysregulations in the activity of ubiquitin E3 ligases, which mediate the selective ubiquitination and subsequent degradation of critical cellular proteins, are associated with different aspects of tumorigenesis, cancer progression, tumor immune infiltration, and response to therapy [3]. Thus, understanding the molecular mechanisms that underlie such aberrations, and discovering the protein targets whose controlled degradation is perturbed in cancer, constitute an attractive area for cancer research. Such cancer-associated alterations in protein stability are becoming therapeutically targetable by the recent technologies in the targeted protein degradation (TPD) field and precision medicine [4, 5].

One exemplar case of a dysregulated E3 ligase in cancer is the recurrent inactivating mutations in a ubiquitin E3 ligase called KEAP1 (kelch-like ECH-associated protein 1) in non-small cell lung cancer (NSCLC) [6, 7]. KEAP1, which encodes for a substrate receptor of a CUL3-RING ubiquitin ligase (CRL3), is considered to be among the top lung cancer drivers. Specifically, this tumor suppressor was shown to be mutated in about 15% of NSCLC patients. Further, KEAP1-mutated NSCLC was previously shown to exhibit immune evasive features, such as lower T cell infiltration and resistance to current immune checkpoint inhibitors [8, 9]. Yet, the underlying mechanisms and the identity of the aberrantly degraded substrates in KEAP1-mutated NSCLC, remain poorly understood.

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Fig. 1: Stabilization of EMSY in KEAP1-mutant NSCLC results in the inactivation of type I interferon signaling, reduction in DNA repair, and lowering of immune cell infiltration.

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Funding

Funding

YM is funded by the European Research Council (ERC- CoG - grant agreement No. 101045613); the Melanoma Research Alliance (MRA - grant agreement No. 826874) and the Cancer Research Institute/Israel Cancer Research Fund CLIP Grant (CRI4351).

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  1. Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel

    Daoud Sheban & Yifat Merbl

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  1. Daoud Sheban
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DS and YM wrote the paper and prepared the figure.

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Correspondence to Yifat Merbl.

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Sheban, D., Merbl, Y. EMSY stabilization in KEAP1-mutant lung cancer disrupts genome stability and type I interferon signaling. Cell Death Differ 30, 1397–1399 (2023). https://doi.org/10.1038/s41418-023-01150-z

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