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Emerging roles of hnRNPA1 in modulating malignant transformation

Advanced Review

Rajat Roy, Yueyang Huang, Michael J. Seckl, Olivier E. Pardo

Published Online: Aug 08 2017

DOI: 10.1002/wrna.1431

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Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA‐binding proteins associated with complex and diverse biological processes such as processing of heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, RNA splicing, transactivation of gene expression, and modulation of protein translation. hnRNPA1 is the most abundant and ubiquitously expressed member of this protein family and has been shown to be involved in multiple molecular events driving malignant transformation. In addition to selective mRNA splicing events promoting expression of specific protein variants, hnRNPA1 regulates the gene expression and translation of several key players associated with tumorigenesis and cancer progression. Here, we will summarize our current knowledge of the involvement of hnRNPA1 in cancer, including its roles in regulating cell proliferation, invasiveness, metabolism, adaptation to stress and immortalization. WIREs RNA 2017, 8:e1431. doi: 10.1002/wrna.1431 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Mechanisms RNA Export and Localization > Nuclear Export/Import

hnRNPA1 structure and function: hnRNPA1 has two RRMs on its N‐terminal, each about 80 nucleotides long. The C‐terminal Glycine‐rich domain contains an RGG (Arg‐Gly‐Gly) box and a nuclear targeting sequence (M9). M9 is responsible for both nuclear import and export. Posttranslational modifications regulate hnRNPA1's RNA‐binding ability, protein–protein interaction and subcellular localization.

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hnRNPA1, hnRNPA2, and PTB modulate metabolism in cancer cells through alternative splicing of PKM: In normal cells, inclusion of exon10 is repressed leading to generation of PKM1. In tumor cells, cMYC can upregulate expression of hnRNPA1, hnRNPA2, and PTB. These then bind and repress exon9, resulting in the inclusion of exon10 and generation of PKM2. The switch from PKM1 to PKM2 potentiates aerobic glycolysis to support tumor growth.

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hnRNPA1 promotes cancer metastasis by regulating the alternative splicing of RAC1: Under normal conditions, hnRNPA1 binds to a silencer component in Exon 3b of the RAC1 mRNA, preventing inclusion of this exon and promoting expression of full‐length RAC1 that controls cytoskeletal rearrangement and cell migration. EGF stimulation facilitates the formation of the SPSB1‐ Elongin B/C‐cullin complex that poly‐ubiquitinates hnRNPA1 on Lys183. This results in decreased affinity of hnRNPA1 toward the silencer component and inclusion of exon3b in mRNAs. The resulting RAC1b protein mediates increase in cellular ROS and EMT.

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CD44 splicing variants and their association to cancer: Blue and red boxes represent constant and alternatively spliced exons, respectively.

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Phosphorylated hnRNPA1 facilitates the RPA‐POT1 switch at telomeric sequence: Stalling of replication fork could result in RPA‐coated single‐strand DNA triggering a DNA damage response (DDR) downstream of ATR signaling. DNA‐PKs‐mediated phosphorylation of hnRNPA1 on Ser95, stimulated in the presence of hTR, allows hnRNPA1 to bind telomeric sequences and remove RPA. POT1, sequestered from the shelterin complex, then replace hnRNPA1 on the exposed overhang and prevent unnecessary DDR.

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Telomere extension requires balanced expression of hnRNPA1 and TERRA: When the levels of hnRNPA1 are significantly lower than those of TERRA, excess TERRA binds to hTR through base pairing, inhibiting telomerase from approaching 3′ telomeric DNA overhangs. When the amount of hnRNPA1 is higher than that of TERRA, excess hnRNPA1 binds directly to the telomeric sequence, preventing the access of telomerase and subsequent inhibition of telomere extension. Balanced levels of the two allows hnRNPA1 to bind TERRA in an inert complex allowing telomerase to access the 3′ telomeric overhangs and mediate efficient telomere maintenance.

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hnRNPA1 regulates cell survival by modulating translation of anti‐apoptotic proteins: Upon activation, S6K2 binds and phosphorylates hnRNPA1 on its Ser4/6 site. The phosphorylated hnRNPA1 binds the IRESs in XIAP and BCLXL mRNAs. The hnRNPA1/mRNA complexes are then exported to the cytoplasm where the mRNAs undergo cap‐independent translation. This coincides with phospho‐hnRNPA1 being recognized by 14‐3‐3 proteins, resulting in recruitment of the sumoylation machinery and sumoylation of hnRNPA1 on Lys183. This enables the reimport of hnRNPA1 into nucleus. hnRNPA1 can also bind the 3′ ARE in the cIAP1 mRNA rather than the IRES site. UV irradiation results in the accumulation of hnRNPA1 in the cytoplasm and increased of this binding with subsequent mRNA degradation and activation of the NFκB pathway.

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