Abstract 3083: Regulation of novel tumor suppressor gene FUS1 expression through 5’- and 3’-UTRs and in response to DNA damage in human lung cancer cells

Abstract

Abstract FUS1 is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. FUS1 mRNA transcripts could be detected on Northern blots in both normal lung and some lung cancer cell lines, but no endogenous FUS1 protein could be detected in a majority of lung cancer cell lines. Loss or reduction of FUS1 expression was observed in all small cell lung cancer and in more than 70 % of non-small cell lung carcinomas and was associated with significantly worse overall patient survival. However, mechanisms regulating FUS1 protein expression and its inactivation in primary lung cancer cells are largely unknown. In this study, we investigated the role of the 5’- and 3’-untranslated regions (UTRs) of the FUS1 gene in the regulation of FUS1 protein expression and determined changes in FUS1 gene and protein expression in response to oncogenic stress in normal lung and cancer cell lines. We constructed a series of expression plasmids containing the FUS1 coding region with or without the intrinsic UTRs and transfected them into normal lung bronchial epithelial and tumor cells to assess their roles in regulation of FUS1 protein expression. We identified some critical structure elements in FUS1 UTRs that could significantly regulate FUS1 protein expression. We found that two small upstream open-reading frames (uORFs) encoding an 8-amino-acid peptide and another 6-amino-acid peptide, respectively, in the 5’UTR of FUS1 could markedly inhibit the translational initiation of FUS1 protein by interfering with the “scanning” of the ribosome initiation complexes. Several secondary RNA structural elements/motifs on the 3’UTR of FUS1 also showed a significant inhibitory effect on FUS1 protein expression. The 3’UTR-mediated regulatory effect on FUS1 proteins expression was differentially detected in normal lung epithelial and fibroblast cells compared to lung cancer cells. We found that FUS1 expression could be induced or activated in the presence of DNA damaging agents, such as UV irradiation, etoposide, and cisplatin. UV irradiation could induce FUS1 protein and mRNA expression independent of the status of FUS1 UTRs. The FUS1 expression activated by DNA damaging agents such as etoposide or cisplatin facilitated FUS1-induced apoptosis, prevented cells from dividing and accelerated cell death. Our results provide new insight into the molecular mechanisms in the regulation of FUS1 expression in lung cancer cells. (Supported by NIH SPORE P50CA70907 and RO1CA116322 grants) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3083.