Heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by increasing protein translation of selected transcripts in cancer cells

Abstract

The heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by coordinating the translation of selected transcripts associated with proliferation and survival. hnRNP A18 binds to and stabilizes the transcripts of pro-survival genes harboring its RNA signature motif in their 3′UTRs. hnRNP A18 binds to ATR, RPA, TRX, HIF-1α and several protein translation factor mRNAs on polysomes and increases de novo protein translation under cellular stress. Most importantly, down regulation of hnRNP A18 decreases proliferation, invasion and migration in addition to significantly reducing tumor growth in two mouse xenograft models, melanoma and breast cancer. Moreover, tissue microarrays performed on human melanoma, prostate, breast and colon cancer indicate that hnRNP A18 is over expressed in 40 to 60% of these malignant tissue as compared to normal adjacent tissue. Immunohistochemistry data indicate that hnRNP A18 is over expressed in the stroma and hypoxic areas of human tumors. These data thus indicate that hnRNP A18 can promote tumor growth in in vivo models by coordinating the translation of pro-survival transcripts to support the demands of proliferating cells and increase survival under cellular stress. hnRNP A18 therefore represents a new target to selectively inhibit protein translation in tumor cells.

Recent progress in the research of cold-inducible RNA-binding protein

“…Currently, CIRP has been demonstrated to positively and post-transcriptionally regulate genes involved in DNA repair [ 34 , 26 , 30 ], cellular redox metabolism [ 27 ], adhesion molecules [ 35 ], circadian mRNAs [ 36 ], reproduction-related genes in testis [ 31 ], telomerase components [ 37 ], HIF-1α [ 38 ] and a number of transcripts associated with the general translational machinery [ 38 ]. In addition to the positive post-transcriptional regulation, a negative role of CIRP in translation has also been reported.…”

“…An RNA-binding protein immunoprecipitation assay in mouse testis revealed that most of the CIRP mRNA targets are associated with translation regulator activity, antioxidant activity, envelopment and reproduction, and that mRNAs bound to CIRP increase their stability [ 31 ]. Through the UniGene database, it was found that the CIRP RNA binding signature motif could be located in the 3′-UTRs of transcripts associated with proliferation, survival and invasion [ 26 , 38 ]. Gene ontology analyses of CIRP-interacting and -regulated transcripts unveiled an enrichment in functions related to cell-cycle progression and adhesion [ 36 ].…”

PARP-1–dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability

“…shock and sepsis (33,34), alternative polyadenylation (35), inhibition of DNA damage-induced apoptosis (36), regulation of telomerase activity (37), and tumorigenesis (38) have also been reported. These findings imply a diverse set of functions for CIRBP under various conditions of cellular stress.…”

Long Noncoding RNAs and RNA‐Binding Proteins in Oxidative Stress, Cellular Senescence, and Age‐Related Diseases

“…hnRNP A0 is phosphorylated by MAPK-activated protein kinase 2 (MK2) and stabilizes GADD45α mRNA during DDR [ 121 ]. In response to UV radiation or hypoxic stress, hnRNP A18 is induced and has protective roles by increasing the expression of UV- or stress-response genes such as replication protein A ( RPA2 ), thioredoxin ( TRX ), or HIF-1α [ 122 , 123 ]. hnRNP A1 is reported to regulate alternative splicing of hdm2 and UVE-triggered translation of Apaf- 1 in response to UV exposure [ 124 ].…”