{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T06:11:42Z","timestamp":1785046302914,"version":"3.55.0"},"reference-count":66,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["109\u2010TMU\u2010WFH\u201005"],"award-info":[{"award-number":["109\u2010TMU\u2010WFH\u201005"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["DP2\u2010107\u201021121\u2010C\u201004"],"award-info":[{"award-number":["DP2\u2010107\u201021121\u2010C\u201004"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["DP2\u2010TMU\u2010112\u20100\u201012"],"award-info":[{"award-number":["DP2\u2010TMU\u2010112\u20100\u201012"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["TMU106\u2010AE1\u2010B31"],"award-info":[{"award-number":["TMU106\u2010AE1\u2010B31"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:p>\n                    Notch signaling is aberrantly activated in approximately 30% of hepatocellular carcinoma (HCC), significantly contributing to tumorigenesis and disease progression. Expression of the major Notch receptor,\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    , is upregulated in HCC cells and correlates with advanced disease stages, although the molecular mechanisms underlying its overexpression remain unclear. Here, we report that expression of the intracellular domain of NOTCH1 (NICD1) is upregulated in HCC cells due to antagonism between the E3\u2010ubiquitin ligase F\u2010box\/WD repeat\u2010containing protein 7 (FBXW7) and the large scaffold protein abnormal spindle\u2010like microcephaly\u2010associated protein (ASPM) isoform 1 (ASPM\u2010i1). Mechanistically, FBXW7\u2010mediated polyubiquitination and the subsequent proteasomal degradation of NICD1 are hampered by the interaction of NICD1 with ASPM\u2010i1, thereby stabilizing NICD1 and rendering HCC cells responsive to stimulation by Notch ligands. Consistently, downregulating ASPM\u2010i1 expression reduced the protein abundance of NICD1 but not its FBXW7\u2010binding\u2010deficient mutant. Reinforcing the oncogenic function of this regulatory module, the forced expression of NICD1 significantly restored the tumorigenic potential of ASPM\u2010i1\u2010deficient HCC cells. Echoing these findings, NICD1 was found to be strongly co\u2010expressed with ASPM\u2010i1 in cancer cells in human HCC tissues (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). In conclusion, our study identifies a novel Notch signaling regulatory mechanism mediated by protein\u2013protein interaction between NICD1, FBXW7, and ASPM\u2010i1 in HCC cells, representing a targetable vulnerability in human HCC.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13589","type":"journal-article","created":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T02:15:13Z","timestamp":1706321713000},"page":"562-579","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>ASPM<\/scp>\n                    stabilizes the\n                    <scp>NOTCH<\/scp>\n                    intracellular domain 1 and promotes oncogenesis by blocking\n                    <scp>FBXW7<\/scp>\n                    binding in hepatocellular carcinoma cells"],"prefix":"10.1002","volume":"18","author":[{"given":"Tze\u2010Sian","family":"Chan","sequence":"first","affiliation":[{"name":"Laboratory of Advanced Molecular 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