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

Abstract

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.

Regulation of monocyte induced cell migration by the RNA binding protein, FXR1

“…6,16,18,22 CDKN1A mRNA was previously demonstrated to be downregulated by FXR1 22 ; accordingly, our microarray data also showed that depletion of FXR1 in serum-grown cells promotes CDKN1A mRNA levels (Fig. 2B, SC , Table S2A).…”

“…5,6,16,[19][20][21][22]24 Our previous data demonstrated a role for an isoform of FXR1 in quiescent (extended > 24 h serum-starved) cells, in upregulating translation (independent of RNA level changes) of a critical cytokine, TNFa 17 that can promote monocyte functions, signaling and differentiation. 26,[28][29][30][31] In early (24 h) serumstarved THP1 acute monocytic leukemic cells, our data revealed altered gene expression mechanisms 33 that are distinct from those in quiescent (extended > 24 h serum-starved) cells.…”

“…1,2 The RNA binding protein, Fragile-X-Mental-Retardation-syndrome-Related protein 1 (FXR1) [3][4][5] is overexpressed and associated with poor clinical outcomes in multiple cancers. 6 FXR1 is similar to Fragile-X-Mental Retardation Protein 1 (FMR1), 4,[7][8][9][10][11][12][13][14] and is implicated at multiple levels of post-transcriptional control, including translation, mRNA stability and transport. 7-10, 12-13, 15-18 FXR1 is associated with negative regulation of specific growth factor and cytokine mRNAs in myocytes 5,[19][20][21][22] and macrophages, 16 which can control development, cell differentiation and cell state specific functions.…”

“…Cytokines like TNFa are transcribed and detected in these conditions; however, the role of FXR1 in regulating specific mRNA levels and expression in serum grown and in early 24 h serum-starved THP1 cells remains to be outlined. Given the effect of FXR1 on cell differentiation 5,[20][21][22] and cancer 6 and its regulation of TNFa cytokine mRNA expression in quiescent, extended serum-starved cells, we examined the role of FXR1 in regulating mRNA levels in serum grown cells and in early (24 h) serum-starved monocytic leukemic cells.…”

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

“…CPSF3, an essential component for converting heteronuclear RNA to mRNA, is associated with cellular stress response 1 protein-mediated cell death [87] and also can be designed as an novel target for control toxoplasmosis[88]. The RNA binding protein FXR1 is a critical regulator of post-transcriptional gene expression in differentiation, development and immunity [89,90]. The THOC1, also known as hHpr1/p84, is a nuclear matrix component protein that binds to the tumor suppressor retinoblastoma protein (pRb).…”