Functional analysis of a novel glioma antigen, EFTUD1

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor. Despite aggressive multimodal treatment with maximal surgical resection followed by temozolomide and radiation, the prognosis for patients with GBM remains poor, with a median survival of 14.6 months and a 3-year survival rate of only 10%.1 The development of new therapies for gliomas is therefore necessary. We previously isolated several candidate glioma antigens using serological identification of antigens by recombinant cDNA expression (SEREX).2,3 Elongation factor Tu GTP-binding domain containing protein 1 (EFTUD1) was identified as one of the isolated antigens. Serological reactivity against recombinant EFTUD1 protein was not observed in 13 healthy individuals. Thus, EFTUD1 was recognized only by the serum from a GBM patient and not by normal donor serum. Following the primary screening by SEREX, in silico analysis of the Oncomine' cancer microarray database showed overexpression of EFTUD1 in glioma samples compared with matched normal samples (see Supplemental Fig. S1). Here, we focused on EFTUD1 as a candidate molecular target for gliomas. EFTUD1 belongs to the GTP-binding elongation factor family and plays an important role in ribosome biogenesis and its translational activation (see Supplemental Fig. S2).4–7 In the nucleus/nucleolus, eukaryotic translation initiation factor 6 (eIF6) binds to 60S-ribosome subunits and exports them to the cytoplasm, where they undergo final maturation.4,7–11 In the cytoplasm, EFTUD1 triggers the GTP-dependent release of eIF6 from 60S-ribosome subunits together with Shwachman-Bodian-Diamond syndrome protein (SBDS).4,7,12,13 The release of eIF6 allows 60S-ribosome subunits to join 40S-ribosome subunits, resulting in the formation of actively translating 80S complexes. Ribosome biogenesis represents a key metabolic requirement in proliferating cells, and its tight regulation is essential for normal cell growth and proliferation.14–21 Consequently, deregulation of this process is thought to contribute to tumor biology.18,21–23 Indeed, overexpression of ribosomal proteins and mutations in genes encoding for proteins that regulate ribosome biogenesis are associated with several cancers.19,20,24 However, the role of EFTUD1 in cancers, including glioma, remains unknown. Here, we analyzed the expression and function of EFTUD1 in glioma to examine the efficacy as a candidate molecular target.