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

T Muramatsu, K-i Kozaki, S Imoto, R Yamaguchi, H Tsuda, T Kawano, N Fujiwara, M Morishita, S Miyano and J Inazawa

Oncogene 2016 35, 5304–5316

Speaker: Chun-I Li (李俊毅)                                                Time: 13:00~14:00, Oct, 26, 2016

Commentator: Dr. Pin Ling (凌斌 老師)                     Place: Room 601

Abstract:

Metastasis is a critical factor contributing to poor prognosis in cancer and driven by multiple genetic or epigenetic alterations and molecular events. Cancer cells could upregulate the proliferation, motility and invasion ability for metastasis via activation of oncogenes and/or the inactivation of tumor suppressor genes[1], leading to the disruption of the environmental matrix and resultant travel to other organs and/or lymph node. However, the detailed mechanisms underlying these processes remain poorly understood, and useful diagnostic markers and molecular target drugs against metastasis remain inadequate so far. It has been reported that dysregulation of the hypusine cascade is relevant to cell proliferation, motility and invasion in cancer[2]. In this study, the authors established a highly metastatic cell subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) by in vivo selection for uncovering the mechanisms of metastasis. They identified deoxyhypusine synthase (DHPS) as a metastasis-associated gene by array-comparative genomic hybridization analysis within the specific amplification at 19p13.2–p13.13 in HOC313-LM. They also demonstrated that DHPS expression promotes cell motility, invasion in vitro, and tumor growth and metastasis in vivo. As we know, DHPS, a catalytic enzyme in hypusine cascade, plays an important role in post-translational modification of eukaryotic translation factor 5A (eIF5A). Hypusination has a critical role in the activation of eIF5A, which functions in protein synthesis. Also, overexpression of eIF5A promotes cell proliferation, motility, invasion and metastasis in various cancers[2]. The authors found that RhoA signaling pathway becomes the critical molecular pathway in the metastatic tumors compared with the primary tumors in vivo by systems biology and ingenuity pathway analyses. Because eIF5A is known as a regulator of the RhoA signaling pathway[3]. The authors investigated whether the hypusine cascade regulates RhoA. Their results showed that the hypusine cascade involving the DHPS-eIF5A-RhoA axis leads to invasion and metastasis in cancer. Furthermore, N1-Guanyl-1,7-diaminoheptane, a hypusination inhibitor, resulted in a significant decrease in tumor formation in vivo and DHPS protein overexpression is associated with recurrence-free overall survival and distant metastasis in esophageal squamous cell carcinoma. The elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in squamous cell carcinoma.

References:

1.    Nguyen, D.X., P.D. Bos, and J. Massague, Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer, 2009. 9(4): p. 274-84.

2.    Kaiser, A., Translational control of eIF5A in various diseases. Amino Acids, 2012. 42(2-3): p. 679-84.

3.    Wang, F.W., X.Y. Guan, and D. Xie, Roles of eukaryotic initiation factor 5A2 in human cancer. Int J Biol Sci, 2013. 9(10): p. 1013-20.