The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma

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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.

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This study was supported in part by a Grant-in Aid for Scientific Research (KAKENHI) for Innovative Areas (22134002, 15H05908) (Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention), Scientific Research (A) (22240090, 25250019), Challenging Exploratory Research (B) (15K18401), Research Activity Start-up (26890012), JSPS Fellows from Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Tailor-Made Medical Treatment with the BioBank Japan Project (BBJ) and the Practical Research for Innovative Cancer Control (15Ack0106017h0002) from Japan Agency for Medical Research and development, AMED and Global Center of Excellence (GCOE) Program for International Research Center for Molecular Science in Tooth and Bone Diseases, from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Correspondence to J Inazawa.

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Muramatsu, T., Kozaki, K., Imoto, S. et al. The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. Oncogene 35, 5304–5316 (2016) doi:10.1038/onc.2016.71

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