| Autor: |
Xian-Yang Qin, Yutaka Furutani, Kento Yonezawa, Nobutaka Shimizu, Miyuki Kato-Murayama, Mikako Shirouzu, Yali Xu, Yumiko Yamano, Akimori Wada, Luc Gailhouste, Rajan Shrestha, Masataka Takahashi, Jeffrey W. Keillor, Ting Su, Wenkui Yu, Shinya Fujii, Hiroyuki Kagechika, Naoshi Dohmae, Yohei Shirakami, Masahito Shimizu, Takahiro Masaki, Tomokazu Matsuura, Harukazu Suzuki, Soichi Kojima |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 14, Iss 6, Pp 1-15 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-023-05847-4 |
| Popis: |
Abstract Transglutaminase 2 (TG2) is a multifunctional protein that promotes or suppresses tumorigenesis, depending on intracellular location and conformational structure. Acyclic retinoid (ACR) is an orally administered vitamin A derivative that prevents hepatocellular carcinoma (HCC) recurrence by targeting liver cancer stem cells (CSCs). In this study, we examined the subcellular location-dependent effects of ACR on TG2 activity at a structural level and characterized the functional role of TG2 and its downstream molecular mechanism in the selective depletion of liver CSCs. A binding assay with high-performance magnetic nanobeads and structural dynamic analysis with native gel electrophoresis and size-exclusion chromatography-coupled multi-angle light scattering or small-angle X-ray scattering showed that ACR binds directly to TG2, induces oligomer formation of TG2, and inhibits the transamidase activity of cytoplasmic TG2 in HCC cells. The loss-of-function of TG2 suppressed the expression of stemness-related genes, spheroid proliferation and selectively induced cell death in an EpCAM+ liver CSC subpopulation in HCC cells. Proteome analysis revealed that TG2 inhibition suppressed the gene and protein expression of exostosin glycosyltransferase 1 (EXT1) and heparan sulfate biosynthesis in HCC cells. In contrast, high levels of ACR increased intracellular Ca2+ concentrations along with an increase in apoptotic cells, which probably contributed to the enhanced transamidase activity of nuclear TG2. This study demonstrates that ACR could act as a novel TG2 inhibitor; TG2-mediated EXT1 signaling is a promising therapeutic target in the prevention of HCC by disrupting liver CSCs. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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