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Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation
Keitaro Kanda, … , Eiichiro Nishi, Hiroshi Seno
Keitaro Kanda, … , Eiichiro Nishi, Hiroshi Seno
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e91316. https://doi.org/10.1172/jci.insight.91316.
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Research Article Oncology

Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

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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.

Authors

Keitaro Kanda, Jiro Sakamoto, Yoshihide Matsumoto, Kozo Ikuta, Norihiro Goto, Yusuke Morita, Mikiko Ohno, Kiyoto Nishi, Koji Eto, Yuto Kimura, Yuki Nakanishi, Kanako Ikegami, Takaaki Yoshikawa, Akihisa Fukuda, Kenji Kawada, Yoshiharu Sakai, Akihiro Ito, Minoru Yoshida, Takeshi Kimura, Tsutomu Chiba, Eiichiro Nishi, Hiroshi Seno

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Figure 1

NRDC is required in ApcMin mouse intestinal tumors.

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NRDC is required in ApcMin mouse intestinal tumors.
(A) Immunostaining f...
(A) Immunostaining for NRDC in human colon cancer specimens. Cancer cells were stained more strongly than the adjacent normal colon epithelium (case 1). (B) qRT-PCR showed that the mRNA level of NRDC (compared with cycle threshold [CT] for GAPDH) was higher in cancer tissues than in adjacent normal colonic tissues (n = 12). *P < 0.05 by paired 2-tailed Student’s t test. (C) Representative H&E staining of the small intestines of ApcMin; Nrdc+/+ and ApcMin; Nrdc–/– mice. (D) The numbers of small intestinal (SI) tumors evaluated in H&E sections of ApcMin; Nrdc+/+ and ApcMin; Nrdc–/– mice (n = 10 and 4, respectively). *P < 0.05 by unpaired 2-tailed Student’s t test. Total number (left) and number in each size fraction (right) are depicted. (E) Macroscopic view of the colon of ApcMin; Nrdc+/+ and ApcMin; Nrdc–/– mice. (F) Representative H&E staining of the rectums of ApcMin; Nrdc+/+ and ApcMin; Nrdc–/– mice. (G) The numbers of colon tumors in ApcMin; Nrdc+/+ and ApcMin; Nrdc–/– mice (n = 10 and 4, respectively). *P < 0.05 by unpaired 2-tailed Student’s t test. (H) Kaplan-Meier analysis demonstrated that ApcMin; Nrdc–/– mice showed a significantly longer survival compared with ApcMin; Nrdc+/+ mice. *P < 0.0001 by log-rank test. All scale bars: 100 μm.

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