دورية أكاديمية
أعرض في EDS

LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion.

التفاصيل البيبلوغرافية
العنوان: LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion.
المؤلفون: Abe T; Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. abet@med.tohoku.ac.jp., Kanno SI; Division of Dynamic Proteome, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan., Niihori T; Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan., Terao M; Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan., Takada S; Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan., Aoki Y; Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. aokiy@med.tohoku.ac.jp.
المصدر: Cell death & disease [Cell Death Dis] 2023 Aug 25; Vol. 14 (8), pp. 556. Date of Electronic Publication: 2023 Aug 25.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Adenocarcinoma of Lung*/genetics , Lung Neoplasms*/genetics, Humans ; Epithelial-Mesenchymal Transition/genetics ; Collagen ; Extracellular Matrix ; Adaptor Proteins, Signal Transducing ; Transcription Factors
مستخلص: Leucine zipper-like transcriptional regulator 1 (LZTR1), a substrate adaptor of Cullin 3 (CUL3)-based E3 ubiquitin ligase, regulates proteostasis of the RAS subfamily. Mutations in LZTR1 have been identified in patients with several types of cancer. However, the role of LZTR1 in tumor metastasis and the target molecules of LZTR1, excluding the RAS subfamily, are not clearly understood. Here, we show that LZTR1 deficiency increases tumor growth and metastasis. In lung adenocarcinoma cells, LZTR1 deficiency induced the accumulation of the RAS subfamily and enhanced cell proliferation, invasion, and xenograft tumor growth. Multi-omics analysis to clarify the pathways related to tumor progression showed that MAPK signaling, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling-related gene ontology terms were enriched in LZTR1 knockout cells. Indeed, LZTR1 deficiency induced high expression of EMT markers under TGF-β1 treatment. Our search for novel substrates that interact with LZTR1 resulted in the discovery of a Kelch-like protein 12 (KLHL12), which is involved in collagen secretion. LZTR1 could inhibit KLHL12-mediated ubiquitination of SEC31A, a component of coat protein complex II (COPII), whereas LZTR1 deficiency promoted collagen secretion. LZTR1-RIT1 and LZTR1-KLHL12 worked independently regarding molecular interactions and did not directly interfere with each other. Further, we found that LZTR1 deficiency significantly increases lung metastasis and promotes ECM deposition around metastatic tumors. Since collagen-rich extracellular matrix act as pathways for migration and facilitate metastasis, increased expression of RAS and collagen deposition may exert synergistic or additive effects leading to tumor progression and metastasis. In conclusion, LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and promoting collagen secretion. The functional inhibition of KLHL12 by LZTR1 provides important evidence that LZTR1 may be a repressor of BTB-Kelch family members. These results provide clues to the mechanism of LZTR1-deficiency carcinogenesis.
(© 2023. The Author(s).)
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المشرفين على المادة: 9007-34-5 (Collagen)
0 (KLHL12 protein, human)
0 (Adaptor Proteins, Signal Transducing)
0 (LZTR1 protein, human)
0 (Transcription Factors)
تواريخ الأحداث: Date Created: 20230825 Date Completed: 20230828 Latest Revision: 20230829
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10457367
DOI: 10.1038/s41419-023-06072-9
PMID: 37626065
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-023-06072-9