RRC ID 50644
著者 Kanda K, Sakamoto J, Matsumoto Y, Ikuta K, Goto N, Morita Y, Ohno M, Nishi K, Eto K, Kimura Y, Nakanishi Y, Ikegami K, Yoshikawa T, Fukuda A, Kawada K, Sakai Y, Ito A, Yoshida M, Kimura T, Chiba T, Nishi E, Seno H.
タイトル Nardilysin controls intestinal tumorigenesis through HDAC1/p53-dependent transcriptional regulation.
ジャーナル JCI Insight
Abstract Colon cancer is a complex disease affected by a combination of genetic and epigenetic factors. Here we demonstrate that nardilysin (N-arginine dibasic convertase; NRDC), a metalloendopeptidase of the M16 family, regulates intestinal tumorigenesis via its nuclear functions. NRDC is highly expressed in human colorectal cancers. Deletion of the Nrdc gene in ApcMin mice crucially suppressed intestinal tumor development. In ApcMin mice, epithelial cell-specific deletion of Nrdc recapitulated the tumor suppression observed in Nrdc-null mice. Moreover, epithelial cell-specific overexpression of Nrdc significantly enhanced tumor formation in ApcMin mice. Notably, epithelial NRDC controlled cell apoptosis in a gene dosage-dependent manner. In human colon cancer cells, nuclear NRDC directly associated with HDAC1, and controlled both acetylation and stabilization of p53, with alterations of p53 target apoptotic factors. These findings demonstrate that NRDC is critically involved in intestinal tumorigenesis through its epigenetic regulatory function, and targeting NRDC may lead to a novel prevention or therapeutic strategy against colon cancer.
巻・号 3(8)
公開日 2018-4-19
DOI 10.1172/jci.insight.91316
PII 91316
PMID 29669932
PMC PMC5931127
MeSH Adult Aged Animals Carcinogenesis / genetics* Carcinogenesis / metabolism Carcinogenesis / pathology Colorectal Neoplasms / metabolism* Disease Models, Animal Epigenomics Female Gene Deletion Histone Deacetylase 1 Humans Male Metalloendopeptidases / metabolism* Metalloendopeptidases / therapeutic use* Mice Middle Aged Neoplasm Staging Tumor Suppressor Protein p53 / metabolism
IF 6.205
引用数 5
リソース情報
ヒト・動物細胞 293T(RCB2202)