title: The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma.
abstract: Metastasis is a critical factor contributing to poor prognosis in cancer, but the underlying mechanisms of metastasis are still poorly understood. We established a highly metastatic cell subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) for uncovering the mechanisms of metastasis, and identified deoxyhypusine synthase (DHPS) as a metastasis-associated gene within the specific amplification at 19p13.2-p13.13 in HOC313-LM. DHPS-mediated hypusine-modification of eukaryotic translation factor 5A facilitated the translation of RhoA, resulting in the activation of the RhoA signaling pathway and leading to not only increased cell motility, invasion and metastasis of cancer cells in vitro, but also increased tumor growth in vivo. Moreover, the use of N1-Guanyl-1,7-diaminoheptane, a DHPS inhibitor, resulted in a significant decrease in tumor formation in vivo. In patients with esophageal squamous cell carcinoma (ESCC), overexpression of DHPS in ESCC tumors was significantly associated with worse recurrence-free survival, and correlated with distant metastasis. The elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in SCC.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Global Center of Excellence (GCOE) Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan.|Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Muramatsu
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Kozaki
authors.affiliation: Department of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.identifier: 0000-0002-2989-308X
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Department of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Department of Basic Pathology, National Defense Medical College, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Department of Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Morishita
authors.affiliation: Department of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Global Center of Excellence (GCOE) Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003959:Diamines / Q000008:administration & dosage; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D003959:Diamines; C066737:RHOA protein, human; C100028:hypusine; C015127:1,7-diaminoheptane; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase; D020742:rhoA GTP-Binding Protein; D008239:Lysine