RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (11), p.3469-3474
• Main Authors: Qian, Jun, Hassanein, Mohamed, Hoeksema, Megan D., Harris, Bradford K., Zou, Yong, Chen, Heidi, Lu, Pengcheng, Eisenberg, Rosana, Wang, Jing, Espinosa, Allan, Ji, Xiangming, Harris, Fredrick T., Rahman, S. M. Jamshedur, Massion, Pierre P.
• Format: Article
• Language: English
• Subjects: Biological Sciences; biomarkers; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Proliferation; chromosomes; Chromosomes, Human, Pair 3 - genetics; DNA Copy Number Variations - genetics; epithelial cells; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Intellectual disabilities; Isoenzymes - genetics; Isoenzymes - metabolism; Lung cancer; lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; oncogenes; Pathogenesis; Physiology; Prognosis; Protein expression; protein kinase C; Protein Kinase C - genetics; Protein Kinase C - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-binding proteins; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Survival Analysis; Treatment Outcome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1421975112

Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene ( FXR1 ) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies. Significance Altered expression of RNA binding proteins might contribute to cancer development. This study reveals the functional implications and clinical relevance of FXR1, an RNA binding protein, in non-small cell lung cancer (NSCLC). Our results demonstrate that FXR1 promotes tumor progression by regulating two other oncogenes within the same chromosome 3q amplicon. To drive tumor progression, FXR1 forms a new complex with protein kinase C, iota, and posttranscriptionally stabilizes the expression of epithelial cell transforming 2. We show that increased FXR1 expression in NSCLC is a candidate biomarker predictive of poor survival and might represent a novel therapeutic target. In addition, FXR1 expression correlates with poor clinical outcome in multiple human cancers, suggesting broader implications of this RNA binding protein in cancer progression.