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