Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A comprehensive understanding of hnRNP A1 role in cancer: new perspectives on binding with noncoding RNA

Cancer Gene Therapy volume 30, pages 394–403 (2023)Cite this article

Subjects

Abstract

The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is the most abundant and ubiquitously expressed member of the heterogeneous nuclear ribonucleoproteins family (hnRNPs). hnRNP A1 is an RNA-binding protein associated with complexes active in diverse biological processes such as RNA splicing, transactivation of gene expression, and modulation of protein translation. It is overexpressed in several cancers, where it actively promotes the expression and translation of several key proteins and regulators associated with tumorigenesis and cancer progression. Interesting recent studies have focused on the RNA-binding property of hnRNP A1 and revealed previously under-explored functions of hnRNP A1 in the processing of miRNAs, and loading non-coding RNAs into exosomes. Here, we will report the recent advancements in our knowledge of the role of hnRNP A1 in the biological processes underlying cancer proliferation and growth, with a particular focus on metabolic reprogramming.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Diagram of the major cellular functions of hnRNP A1.
Fig. 2: Structure and post-translational modification of hnRNPA1.
Fig. 3: Onco-suppressor miRNAs and hnRNP A1 overexpression in different tumor types.
Fig. 4: hnRNPA1 promotes cancer metastasis by regulating the alternative splicing of PKM pre-mRNA.
Fig. 5: hnRNP A1 controls miRNA processing in tumors.
Fig. 6: The interrelationship between hnRNP A1 and ncRNA in tumors.

Similar content being viewed by others

References

  1. Beyer AL, Christensen ME, Walker BW, Le Stourgeon WM. Identification and characterization of the packaging proteins of core 40S hnRNP particles. Cell. 1977;11:127–38. https://doi.org/10.1016/0092-8674(77)90323-3

    Article  CAS  PubMed  Google Scholar 

  2. Kaur R, Lal SK. The multifarious roles of heterogeneous ribonucleoprotein A1 in viral infections. Rev Med Virol. 2020;30:e2097 https://doi.org/10.1002/rmv.2097

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhang L, Chen Q, An W, Yang F, Maguire EM, Chen D, et al. Novel pathological role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in vascular smooth muscle cell function and neointima hyperplasia. Arterioscler Thromb Vasc Biol. 2017;37:2182–94. https://doi.org/10.1161/ATVBAHA.117.310020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Clarke JP, Thibault PA, Salapa HE, Levin MC. A comprehensive analysis of the role of hnRNP A1 function and dysfunction in the pathogenesis of neurodegenerative disease. Front Mol Biosci. 2021;8:1–19. https://doi.org/10.3389/fmolb.2021.659610

    Article  CAS  Google Scholar 

  5. Picchiarelli G, Dupuis L. Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases. Cell Stress. 2020;4:76–91. https://doi.org/10.15698/cst2020.04.217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Savarese M, Sarparanta J, Vihola A, Jonson PH, Johari M, Rusanen S, et al. Panorama of the distal myopathies. Acta Myol. 2020;39:245–65. https://doi.org/10.36185/2532-1900-028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bandziulis RJ, Swanson MS, Dreyfuss G. RNA-binding proteins as developmental regulators. Genes Dev. 1989;3:431–7. https://doi.org/10.1101/gad.3.4.431

    Article  CAS  PubMed  Google Scholar 

  8. Mayeda A, Munroe SH, Cáceres JF, Krainer AR. Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins. EMBO J 1994;13:5483–95. https://doi.org/10.1002/j.1460-2075.1994.tb06883.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kiledjian M, Dreyfuss G. Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J 1992;11:2655–64. https://doi.org/10.1002/j.1460-2075.1992.tb05331.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cartegni L, Maconi M, Morandi E, Cobianchi F, Riva S, Biamonti G. hnRNP A1 selectively interacts through its Gly-rich domain with different RNA-binding proteins. J Mol Biol. 1996;259:337–48. https://doi.org/10.1006/jmbi.1996.0324

    Article  CAS  PubMed  Google Scholar 

  11. Siomi H, Matunis MJ, Michael WM, Dreyfuss G. The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. Nucleic Acids Res. 1993;21:1193–8. https://doi.org/10.1093/nar/21.5.1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Izaurralde E, Jarmolowski A, Beisel C, Mattaj IW, Dreyfuss, Fischer U. A role for the M9 transport signal of hnRNP A1 in mRNA nuclear export. J Cell Biol. 1997;137:27–35. https://doi.org/10.1083/jcb.137.1.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Michael WM, Eder PS, Dreyfuss G. The K nuclear shuttling domain: a novel signal for nuclear import and nuclear export in the hnRNP K protein. EMBO J 1997;16:3587–98. https://doi.org/10.1093/emboj/16.12.3587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Suzuki M, Iijima M, Nishimura A, Tomozoe Y, Kamei D, Yamada M. Two separate regions essential for nuclear import of the hnRNP D nucleocytoplasmic shuttling sequence. FEBS J. 2005;272:3975–87. https://doi.org/10.1111/j.1742-4658.2005.04820.x

    Article  CAS  PubMed  Google Scholar 

  15. Kamath RV, Leary DJ, Huang S. Nucleocytoplasmic shuttling of polypyrimidine tract-binding protein is uncoupled from RNA export. Mol Biol Cell. 200;12:3808–20. https://doi.org/10.1091/mbc.12.12.3808

  16. Buvoli M, Cobianchi F, Bestagno MG, Mangiarotti A, Bassi MT, Biamonti G, et al. Alternative splicing in the human gene for the core protein A1 generates another hnRNP protein. EMBO J 1990;9:1229–35. https://doi.org/10.1002/j.1460-2075.1990.tb08230.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Erdem M, Ozgul İ, Dioken DN, Gurcuoglu I, Guntekin Ergun S, Cetin-Atalay R, et al. Identification of an mRNA isoform switch for HNRNPA1 in breast cancers. Sci Rep. 2021;11:1–15. https://doi.org/10.1038/s41598-021-04007-y

    Article  CAS  Google Scholar 

  18. Nadler SG, Merrill BM, Roberts WJ, Keating KM, Lisbin MJ, Barnett SF, et al. Interactions of the A1 heterogeneous nuclear ribonucleoprotein and its proteolytic derivative, UP1, with RNA and DNA: evidence for multiple RNA binding domains and salt-dependent binding mode transitions. Biochemistry. 1991;30:2968–76. https://doi.org/10.1021/bi00225a034

    Article  CAS  PubMed  Google Scholar 

  19. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467–73. https://doi.org/10.1038/nature11922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Siomi H, Dreyfuss G. A nuclear localization domain in the hnRNP A1 protein. J Cell Biol. 1995;129:551–60. https://doi.org/10.1083/jcb.129.3.551

    Article  CAS  PubMed  Google Scholar 

  21. Allemand E, Guil S, Myers M, Moscat J, Caceres JF, Krainer AR. Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock. Proc Natl Acad Sci USA. 2005;102:3605–10. https://doi.org/10.1073/pnas.0409889102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rebane A, Aab A, Steitz JA. Transportins 1 and 2 are redundant nuclear import factors for hnRNP A1 and HuR. RNA. 2004;10:590–9. https://doi.org/10.1261/rna.5224304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rajpurohit R, Paik WK, Kim S. Effect of enzymic methylation of heterogeneous ribonucleoprotein particle A1 on its nucleic-acid binding and controlled proteolysis. Biochem J 1994;304:903–9. https://doi.org/10.1042/bj3040903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ong S, Mittler G, Mann M. Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat Methods. 2004;1:119–26. https://doi.org/10.1038/nmeth715

    Article  CAS  PubMed  Google Scholar 

  25. Li WJ, He YH, Yang JJ, Hu GS, Lin YA, Ran T, et al. Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth. Nat Commun. 2021;12:1946 https://doi.org/10.1038/s41467-021-21963-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Guccione E, Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol. 2019;20:642–57. https://doi.org/10.1038/s41580-019-0155-x

    Article  CAS  PubMed  Google Scholar 

  27. Gao G, Dhar S, Bedford MT. PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1. Nucleic Acids Res. 2017;45:4359–69. https://doi.org/10.1093/nar/gkw1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jarrold J, Davies CC. PRMTs and Arginine methylation: cancer’s best-kept secret? Trends Mol Med. 2019;25:993–1009. https://doi.org/10.1016/j.molmed.2019.05.007

    Article  CAS  PubMed  Google Scholar 

  29. Cobianchi F, Calvio C, Stoppini M, Buvoli M, Riva S. Phosphorylation of human hnRNP protein A1 abrogates in vitro strand annealing activity. Nucleic Acids Res. 1993;21:949–55. https://doi.org/10.1093/nar/21.4.949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jo OD, Martin J, Bernath A, Masri J, Lichtenstein A, Gera J. Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling. J Biol Chem. 2008;283:23274–87. https://doi.org/10.1074/jbc.M801185200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van der Houven van Oordt W, Diaz-Meco MT, Lozano J, Krainer AR, Moscat J, et al. The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J Cell Biol. 2000;149:307–16. https://doi.org/10.1083/jcb.149.2.307

    Article  PubMed  PubMed Central  Google Scholar 

  32. Buxadé M, Parra JL, Rousseau S, Shpiro N, Marquez R, Morrice N, et al. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity. 2005;23:177–89. https://doi.org/10.1016/j.immuni.2005.06.009

    Article  CAS  PubMed  Google Scholar 

  33. Shimada N, Rios I, Moran H, Sayers B, Hubbard K. p38 MAP kinase-dependent regulation of the expression level and subcellular distribution of heterogeneous nuclear ribonucleoprotein A1 and its involvement in cellular senescence in normal human fibroblasts. RNA Biol. 2009;6:293–304. https://doi.org/10.4161/rna.6.3.8497

    Article  CAS  PubMed  Google Scholar 

  34. Sun Y, Luo M, Chang G, Ren W, Wu K, Li X, et al. Phosphorylation of Ser6 in hnRNPA1 by S6K2 regulates glucose metabolism and cell growth in colorectal cancer. Oncol Lett. 2017;14:7323–31. https://doi.org/10.3892/ol.2017.7085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Municio MM, Lozano J, Sanchez P, Moscat J, Diaz-Meco MT. Identification of heterogeneous ribonucleoprotein A1 as a novel substrate for protein kinase C zeta. J Biol Chem. 1995;270:15884–91. https://doi.org/10.1074/jbc.270.26.15884

    Article  CAS  PubMed  Google Scholar 

  36. Ting NS, Pohorelic B, Yu Y, Lees-Miller SP, Beattie TL. The human telomerase RNA component, hTR, activates the DNA-dependent protein kinase to phosphorylate heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res. 2009;37:6105–15. https://doi.org/10.1093/nar/gkp636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sui J, Lin YF, Xu K, Lee KJ, Wang D, Chen BPC. DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication. Nucl Acids Res. 2015;43:5971–83. https://doi.org/10.1093/nar/gkv539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Choi YH, Lim JK, Jeong MW, Kim KT. HnRNP A1 phosphorylated by VRK1 stimulates telomerase and its binding to telomeric DNA sequence. Nucleic Acids Res. 2012;40:8499–518. https://doi.org/10.1093/nar/gks634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roy R, Durie D, Li H, Liu BQ, Skehel JM, Mauri F, et al. hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling. Nucleic Acids Res. 2014;42:12483–97. https://doi.org/10.1093/nar/gku953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fang J, Bolanos LC, Choi K, Liu X, Christie S, Akunuru S, et al. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol. 2017;18:236–45. https://doi.org/10.1038/ni.3654

    Article  CAS  PubMed  Google Scholar 

  41. Wang F, Fu X, Chen P, Wu P, Fan X, Li N, et al. SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling. Cell Res. 2017;27:540–58. https://doi.org/10.1038/cr.2017.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yang H, Zhu R, Zhao X, Liu L, Zhou Z, Zhao L, et al. Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma. Oncogene. 2019;38:4915–31. https://doi.org/10.1038/s41388-019-0764-z

    Article  CAS  PubMed  Google Scholar 

  43. Duan Y, Du A, Gu J, Duan G, Wang C, Gui X, et al. PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins. Cell Res. 2019;29:233–47. https://doi.org/10.1038/s41422-019-0141-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov 2022;12:31–46. https://doi.org/10.1158/2159-8290.CD-21-1059

    Article  CAS  PubMed  Google Scholar 

  45. Yu L, Chen X, Sun X, Wang L, Chen S. The glycolytic switch in tumors: how many players are involved. J Cancer. 2017;8:3430–40. https://doi.org/10.7150/jca.21125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Clemens MJ. Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene. 2004;23:3180–8. https://doi.org/10.1038/sj.onc.1207544

    Article  CAS  PubMed  Google Scholar 

  47. Voeller D, Rahman L, Zajac-Kaye M. Elevated levels of thymidylate synthase linked to neoplastic transformation of mammalian cells. Cell Cycle. 2004;3:1005–7. https://doi.org/10.4161/cc.3.8.1064

    Article  CAS  PubMed  Google Scholar 

  48. Damiano F, Giannotti L, Gnoni GV, Siculella L, Gnoni A. Quercetin inhibition of SREBPs and ChREBP expression results in reduced cholesterol and fatty acid synthesis in C6 glioma cells. Int J Biochem Cell Biol. 2019;117:1–7. https://doi.org/10.1016/j.biocel.2019.105618

    Article  CAS  Google Scholar 

  49. Boukakis G, Patrinou-Georgoula M, Lekarakou M, Valavanis C, Guialis A. Deregulated expression of hnRNP A/B proteins in human non-small cell lung cancer: parallel assessment of protein and mRNA levels in paired tumour/non-tumour tissues. BMC Cancer. 2010;10:434 https://doi.org/10.1186/1471-2407-10-434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brockstedt E, Rickers A, Kostka S, Laubersheimer A, Dorken B, Wittmann-Liebold B, et al. Identification of apoptosis-associated proteins in a human Burkitt lymphoma cell line. Cleavage of heterogeneous nuclear ribonucleoprotein A1 by caspase 3. J Biol Chem. 1998;273:28057–64. https://doi.org/10.1074/jbc.273.43.28057

    Article  CAS  PubMed  Google Scholar 

  51. Chen Y, Liu J, Wang W, Xiang L, Wang J, Liu S, et al. High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer. Oncol Rep. 2018;39:1693–701. https://doi.org/10.3892/or.2018.6273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A, et al. hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol. 2002;22:2255–66. https://doi.org/10.1128/MCB.22.7.2255-2266.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pino I, Pio R, Toledo G, Zabalegui N, Vicent S, Rey N, et al. Altered patterns of expression of members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family in lung cancer. Lung Cancer. 2003;41:131–43. https://doi.org/10.1016/S0169-5002(03)00193-4

    Article  PubMed  Google Scholar 

  54. Shi Y, Frost PJ, Hoang BQ, Benavides A, Sharma S, Gera JF, et al. IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res. 2008;68:10215–22. https://doi.org/10.1074/jbc.M110.153221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ushigome M, Ubagai T, Fukuda H, Tsuchiya N, Sugimura T, Takatsuka J, et al. Up-regulation of hnRNP A1 gene in sporadic human colorectal cancers. Int J Oncol. 2005;26:635–40. https://doi.org/10.3892/ijo.26.3.635

    Article  CAS  PubMed  Google Scholar 

  56. Ryu HG, Jung Y, Lee N, Seo JY, Kim SW, Lee KH, et al. HNRNP A1 promotes lung cancer cell proliferation by modulating VRK1 translation. Int J Mol Sci. 2021;22:5506 https://doi.org/10.3390/ijms22115506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yu C, Guo J, Liu Y, Jia J, Jia R, Fan M. Oral squamous cancer cell exploits hnRNP A1 to regulate cell cycle and proliferation. J Cell Physiol. 2015;230:2252–61. https://doi.org/10.1002/jcp.24956

    Article  CAS  PubMed  Google Scholar 

  58. Zhou ZJ, Dai Z, Zhou SL, Fu XT, Zhao YM, Shi YH, et al. Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer. 2013;132:1080–9. https://doi.org/10.1002/ijc.27742

    Article  CAS  PubMed  Google Scholar 

  59. Otsuka K, Yamamoto Y, Ochiya T. Regulatory role of resveratrol, a microRNA-controlling compound, in HNRNPA1 expression, which is associated with poor prognosis in breast cancer. Oncotarget. 2018;9:24718–30. https://doi.org/10.18632/oncotarget.25339

    Article  PubMed  PubMed Central  Google Scholar 

  60. Chen M, Zhang J, Manley JL. Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA. Cancer Res. 2010;70:8977–80. https://doi.org/10.1158/0008-5472.CAN-10-2513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun Y, Zhao X, Zhou Y, Hu Y. miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncol Rep. 2012;28:1346–52. https://doi.org/10.3892/or.2012.1958

    Article  CAS  PubMed  Google Scholar 

  62. Fu R, Yang P, Amin S, Li Z. A novel miR-206/hnRNPA1/PKM2 axis reshapes the Warburg effect to suppress colon cancer growth. Biochem Biophys Res Commun. 2020;531:465–71. https://doi.org/10.1016/j.bbrc.2020.08.019

    Article  CAS  PubMed  Google Scholar 

  63. Song L, Lin HS, Gong JN, Han H, Wang XS, Su R, et al. microRNA-451-modulated hnRNP A1 takes a part in granulocytic differentiation regulation and acute myeloid leukemia. Oncotarget. 2017;8:55453–66. https://doi.org/10.18632/oncotarget.19325

    Article  PubMed  PubMed Central  Google Scholar 

  64. Rodriguez-Aguayo C, Monroig PDC, Redis RS, Bayraktar E, Almeida MI, Ivan C, et al. Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer. Cell Disco. 2017;3:17029 https://doi.org/10.1038/celldisc.2017.29

    Article  CAS  Google Scholar 

  65. Chen FR, Sha SM, Wang SH, Shi HT, Dong L, Liu D, et al. RP11-81H3.2 promotes gastric cancer progression through miR-339-HNRNPA1 interaction network. Cancer Med. 2020;9:2524–34. https://doi.org/10.1002/cam4.2867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wen YA, Xiong X, Zaytseva YY, Napier DL, Vallee E, Li AT, et al. Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer. Cell Death Dis. 2018;9:265 https://doi.org/10.1038/s41419-018-0330-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3. https://doi.org/10.1038/nature06734

    Article  CAS  PubMed  Google Scholar 

  68. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463:364–8. https://doi.org/10.1038/nature08697

    Article  CAS  PubMed  Google Scholar 

  69. Zhu HE, Li T, Shi S, Chen DX, Chen W, Chen H. ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation. J Exp Clin Cancer Res. 2021;40:64 https://doi.org/10.1186/s13046-021-01858-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lan Z, Yao X, Sun K, Li A, Liu S, Wang X. The interaction between lncRNA SNHG6 and hnRNPA1 contributes to the growth of colorectal cancer by enhancing aerobic glycolysis through the regulation of alternative splicing of PKM. Front Oncol. 2020;10:363 https://doi.org/10.3389/fonc.2020.00363

    Article  PubMed  PubMed Central  Google Scholar 

  71. Yan Q, Zeng P, Zhou X, Zhao X, Chen R, Qiao J, et al. RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing. Oncogene. 2021;40:2635–50. https://doi.org/10.1038/s41388-021-01666-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Huang JZ, Chen M, Chen D, Gao XC, Zhu S, Huang H, et al. A peptide encoded by a putative lncRNA HOXB-AS3 suppresses colon cancer growth. Mol Cell. 2017;68:171–84. https://doi.org/10.1016/j.molcel.2017.09.015

    Article  CAS  PubMed  Google Scholar 

  73. Sun G, Zhou H, Chen K, Zeng J, Zhang Y, Yan L, et al. HnRNP A1-mediated alternative splicing of CCDC50 contributes to cancer progression of clear cell renal cell carcinoma via ZNF395. J Exp Clin Cancer Res. 2020;39:116 https://doi.org/10.1186/s13046-020-01606-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Senbanjo LT, Chellaiah MA. CD44: A multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front Cell Dev Biol. 2017;5:18 https://doi.org/10.3389/fcell.2017.00018

    Article  PubMed  PubMed Central  Google Scholar 

  75. Saito S, Okabe H, Watanabe M, Ishimoto T, Iwatsuki M, Baba Y, et al. CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer. Oncol Rep. 2013;29:1570–8. https://doi.org/10.3892/or.2013.2273

    Article  CAS  PubMed  Google Scholar 

  76. Li Z, Chen K, Jiang P, Zhang X, Li X. CD44v/CD44s expression patterns are associated with the survival of pancreatic carcinoma patients. Diagn Pathol. 2014;9:79 https://doi.org/10.1186/1746-1596-9-79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Loh TJ, Moon H, Cho S, Jang H, Liu YC, Tai H, et al. CD44 alternative splicing and hnRNP A1 expression are associated with the metastasis of breast cancer. Oncol Rep. 2015;34:1231–8. https://doi.org/10.3892/or.2015.4110

    Article  CAS  PubMed  Google Scholar 

  78. Qiao GL, Song LN, Deng ZF, Chen Y, Ma LJ. Prognostic value of CD44v6 expression in breast cancer: a meta-analysis. Onco Targets Ther. 2018;11:5451–7. https://doi.org/10.2147/OTT.S156101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nadiminty N, Tummala R, Liu C, Lou W, Evans CP, Gao AC. NF-kappaB2/p52:c-Myc:hnRNPA1 pathway regulates expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer. Mol Cancer Ther. 2015;14:1884–95. https://doi.org/10.1158/1535-7163.MCT-14-1057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Svitkin YV, Ovchinnikov LP, Dreyfuss G, Sonenberg N. General RNA binding proteins render translation cap dependent. EMBO J 1996;15:7147–55. https://doi.org/10.1002/j.1460-2075.1996.tb01106.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11:113–27. https://doi.org/10.1038/nrm2838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Martinez-Salas E, Pineiro D, Fernandez N. Alternative mechanisms to initiate translation in eukaryotic mRNAs. Comp Funct Gen. 2012;2012:1–12. https://doi.org/10.1155/2012/391546

    Article  CAS  Google Scholar 

  83. Zhao J, Li Y, Wang C, Zhang H, Zhang H, Jiang B, et al. IRESbase: a comprehensive database of experimentally validated internal ribosome entry sites. Genomics Proteom Bioinforma. 2020;18:129–39. https://doi.org/10.1016/j.gpb.2020.03.001

    Article  Google Scholar 

  84. Thakor N, Holcik M. IRES-mediated translation of cellular messenger RNA operates in eIF2α- independent manner during stress. Nucleic Acids Res. 2012;40:541–52. https://doi.org/10.1093/nar/gkr701

    Article  CAS  PubMed  Google Scholar 

  85. Damiano F, Rochira A, Tocci R, Alemanno S, Gnoni A, Siculella L. hnRNP A1 mediates the activation of the IRES-dependent SREBP-1a mRNA translation in response to endoplasmic reticulum stress. Biochem J. 2013;449:543–53. https://doi.org/10.1042/BJ20120906

    Article  CAS  PubMed  Google Scholar 

  86. Damiano F, Testini M, Tocci R, Gnoni GV, Siculella L. Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl2. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863:388–98. https://doi.org/10.1016/j.bbalip.2018.01.006

    Article  CAS  PubMed  Google Scholar 

  87. Siculella L, Giannotti L, Testini M, Gnoni GV, Damiano F. In steatotic cells, ATP-citrate lyase mRNA is efficiently translated through a cap-independent mechanism, contributing to the stimulation of de novo lipogenesis. Int J Mol Sci. 2020;21:1206–20. https://doi.org/10.3390/ijms21041206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Godet AC, David F, Hantelys F, Tatin F, Lacazette E, Garmy-Susini B, et al. IRES trans-acting factors, key actors of the stress response. Int J Mol Sci. 2019;20:924–82. https://doi.org/10.3390/ijms20040924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bonnal S, Pileur F, Orsini C, Parker F, Pujol F, Prats AC, et al. Heterogeneous nuclear ribonucleoprotein A1 is a novel internal ribosome entry site trans-acting factor that modulates alternative initiation of translation of the fibroblast growth factor 2 mRNA. J Biol Chem. 2005;280:4144–53. https://doi.org/10.1074/jbc.M411492200

    Article  CAS  PubMed  Google Scholar 

  90. Damiano F, Alemanno S, Gnoni GV, Siculella L. Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site. Biochem J. 2010;429:603–12. https://doi.org/10.1042/BJ20091827

    Article  CAS  PubMed  Google Scholar 

  91. Kim HJ, Lee HR, Seo JY, Ryu HG, Lee KH, Kim DY, et al. Heterogeneous nuclear ribonucleoprotein A1 regulates rhythmic synthesis of mouse Nfil3 protein via IRES-mediated translation. Sci Rep. 2017;7:1–15. https://doi.org/10.1038/srep42882

    Article  CAS  Google Scholar 

  92. Charpentier M, Dupré E, Fortun A, Briand F, Maillasson M, Com E, et al. HnRNP-A1 binds to the IRES of MELOE-1 antigen to promote MELOE-1 translation in stressed melanoma cells. Mol Oncol. 2022;16:594–606. https://doi.org/10.1002/1878-0261.13088

    Article  CAS  PubMed  Google Scholar 

  93. Kunze MM, Benz F, Brauss TF, Lampe S, Weigand JE, Braun J, et al. sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism. Biochim Biophys Acta. 2016;1859:848–59. https://doi.org/10.1016/j.bbagrm.2016.05.005

    Article  CAS  PubMed  Google Scholar 

  94. Ruggero D, Sonenberg N. The Akt of translational control. Oncogene. 2005;24:7426–34. https://doi.org/10.1038/sj.onc.1209098

    Article  CAS  PubMed  Google Scholar 

  95. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–32. https://doi.org/10.1016/j.semcancer.2019.07.009

    Article  CAS  PubMed  Google Scholar 

  96. Huang WC, Li X, Liu J, Lin J, Chung LW. Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells. Mol Cancer Res. 2012;10:133–42. https://doi.org/10.1158/1541-7786.MCR-11-0206

    Article  CAS  PubMed  Google Scholar 

  97. Siculella L, Tocci R, Rochira A, Testini M, Gnoni A, Damiano F. Lipid accumulation stimulates the cap-independent translation of SREBP-1a mRNA by promoting hnRNP A1 binding to its 5′-UTR in a cellular model of hepatic steatosis. Biochim Biophys Acta. 2016;1861:471–81. https://doi.org/10.1016/j.bbalip.2016.02.003

    Article  CAS  PubMed  Google Scholar 

  98. Lewis SM, Veyrier A, Hosszu Ungureanu N, Bonnal S, Vagner S, Holcik M. Subcellular relocalization of a trans-acting factor regulates XIAP IRES-dependent translation. Mol Biol Cell. 2007;18:1302–11. https://doi.org/10.1091/mbc.e06-06-0515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cammas A, Pileur F, Bonnal S, Lewis SM, Leveque N, Holcik M, et al. Cytoplasmic relocalization of heterogeneous nuclear ribonucleoprotein A1 controls translation initiation of specific mRNAs. Mol Biol Cell 2007;18:5048–59. https://doi.org/10.1091/mbc.e07-06-0603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zeng J, Xu H, Huang C, Sun Y, Xiao H, Yu G, et al. CD46 splice variant enhances translation of specific mRNAs linked to an aggressive tumor cell phenotype in bladder cancer. Mol Ther Nucleic Acids. 2021;24:140–53. https://doi.org/10.1016/j.omtn.2021.02.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wall ML, Lewis SM. Methylarginines within the RGG-motif region of hnRNP A1 affect its IRES trans-acting factor activity and are required for hnRNP A1 stress granule localization and formation. J Mol Biol. 2017;429:295–307. https://doi.org/10.1016/j.jmb.2016.12.011

    Article  CAS  PubMed  Google Scholar 

  102. Liu X, Zhou Y, Lou Y, Zhong H. Knockdown of HNRNPA1 inhibits lung adenocarcinoma cell proliferation through cell cycle arrest at G0/G1 phase. Gene. 2016;576:791–97. https://doi.org/10.1016/j.gene.2015.11.009

    Article  CAS  PubMed  Google Scholar 

  103. Kolenda T, Guglas K, Kopczyńska M, Sobocińska J, Teresiak A, Bliźniak R, et al. Good or not good: Role of miR-18a in cancer biology. Rep Pr Oncol Radiother. 2020;25:808–19. https://doi.org/10.1016/j.rpor.2020.07.006

    Article  Google Scholar 

  104. Michlewski G, Guil S, Cáceres JF. Stimulation of pri-miR-18a processing by hnRNP A1. Adv Exp Med Biol. 2011;700:28–35. https://doi.org/10.1007/978-1-4419-7823-3_3

    Article  PubMed  Google Scholar 

  105. Mori F, Ferraiuolo M, Santoro R, Sacconi A, Goeman F, Pallocca M, et al. Multitargeting activity of miR-24 inhibits long-term melatonin anticancer effects. Oncotarget. 2016;7:20532–48. https://doi.org/10.18632/oncotarget.7978

    Article  PubMed  PubMed Central  Google Scholar 

  106. Michlewski G, Cáceres JF. Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol. 2010;17:1011–8. https://doi.org/10.1038/nsmb.1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chirshev E, Oberg KC, Ioffe YJ, Unternaehrer JJ. Let-7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer. Clin Transl Med. 2019;8:24–37. https://doi.org/10.1186/s40169-019-0240-y

    Article  PubMed  PubMed Central  Google Scholar 

  108. Hao A, Wang Y, Zhang X, Li J, Li Y, Li D, et al. Long non-coding antisense RNA HYOU1-AS is essential to human breast cancer development through competitive binding hnRNPA1 to promote HYOU1 expression. Biochim Biophys Acta. 2021;1868:1–12. https://doi.org/10.1016/j.bbamcr.2021.118951

    Article  CAS  Google Scholar 

  109. Wang JM, Jiang JY, Zhang DL, Du X, Wu T, Du ZX. HYOU1 facilitates proliferation, invasion and glycolysis of papillary thyroid cancer via stabilizing LDHB mRNA. J Cell Mol Med. 2021;25:4814–25. https://doi.org/10.1111/jcmm.16453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wen Z, Lian L, Ding H, Hu Y, Xiao Z, Xiong K, et al. LncRNA ANCR promotes hepatocellular carcinoma metastasis through upregulating HNRNPA1 expression. RNA Biol. 2020;17:381–94. https://doi.org/10.1080/15476286.2019.1708547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gao X, Wan Z, Wei M, Dong Y, Zhao Y, Chen X, et al. Chronic myelogenous leukemia cells remodel the bone marrow niche via exosome mediated transfer of miR-320. Theranostics. 2019;9:5642–56. https://doi.org/10.1080/15476286.2019.1708547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Qin X, Guo H, Wang X, Zhu X, Yan M, Wang X, et al. Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5. Genome Biol. 2019;20:12–32. https://doi.org/10.1186/s13059-018-1604-0

    Article  PubMed  PubMed Central  Google Scholar 

  113. Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemoresistance in gastric cancer. Mol Cancer. 2020;19:43–59. https://doi.org/10.1186/s12943-020-01168-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang Z, Lin M, He L, Qi H, Shen J, Ying K. Exosomal lncRNA SCIRT/miR-665 transferring promotes lung cancer cell metastasis through the inhibition of HEYL. J Oncol. 2021;2021:13. https://doi.org/10.1155/2021/9813773

  115. Li Y, Zhang J, Li S, Guo C, Li Q, Zhang X, et al. Heterogeneous nuclear ribonucleoprotein a1 loads batched tumor-promoting micrornas into small extracellular vesicles with the assist of caveolin-1 in A549 cells. Front Cell Dev Biol. 2021;9:1–15. https://doi.org/10.3389/fcell.2021.687912

    Article  CAS  Google Scholar 

  116. Cho JH, Shin JC, Cho JJ, Choi YH, Shim JH, Chae JI. Esculetin (6,7-dihydroxycoumarin): A potential cancer chemopreventive agent through suppression of Sp1 in oral squamous cancer cells. Int J Oncol. 2015;46:265–71. https://doi.org/10.3892/ijo.2014.2700

    Article  CAS  PubMed  Google Scholar 

  117. Jiang R, Su G, Chen X, Chen S, Li Q, Xie B, et al. Esculetin inhibits endometrial cancer proliferation and promotes apoptosis via hnRNPA1 to downregulate BCLXL and XIAP. Cancer Lett. 2021;521:308–21. https://doi.org/10.1016/j.canlet.2021.08.039

    Article  CAS  PubMed  Google Scholar 

  118. Wu H, Cui M, Li C, Li H, Dai Y, Cui K, et al. Kaempferol reverses aerobic glycolysis via miR-339-5p-Mediated PKM alternative splicing in colon cancer cells. J Agric Food Chem. 2021;69:3060–8. https://doi.org/10.1021/acs.jafc.0c07640

    Article  CAS  PubMed  Google Scholar 

  119. Tummala R, Lou W, Gao AC, Nadiminty N. Quercetin targets hnRNPA1 to overcome enzalutamide resistance in prostate cancer cells. Mol Cancer Ther. 2017;16:2770–79. https://doi.org/10.1158/1535-7163.MCT-17-0030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Grasso D, Zampieri LX, Capelôa T, Van de Velde JA, Sonveaux P. Mitochondria in cancer. Cell Stress. 2020;4:114–46. https://doi.org/10.15698/cst2020.06.221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy

    Luisa Siculella, Laura Giannotti, Benedetta Di Chiara Stanca, Francesco Spedicato, Matteo Calcagnile, Stefano Quarta & Fabrizio Damiano

  2. Institute of Clinical Physiology (IFC), National Research Council (CNR), Lecce, Italy

    Marika Massaro

Authors
  1. Luisa Siculella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Giannotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benedetta Di Chiara Stanca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesco Spedicato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matteo Calcagnile
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefano Quarta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marika Massaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fabrizio Damiano
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FD designed the concept. LG, BDCS, FS, SQ, MM, MC, and FD searched the literature. FD, MM, and LS wrote the manuscript. LG, BDCS, MC, and FS created the figures. FD, LS, MM, and SQ revised the manuscript. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Fabrizio Damiano.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Siculella, L., Giannotti, L., Di Chiara Stanca, B. et al. A comprehensive understanding of hnRNP A1 role in cancer: new perspectives on binding with noncoding RNA. Cancer Gene Ther 30, 394–403 (2023). https://doi.org/10.1038/s41417-022-00571-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-022-00571-1

This article is cited by

Search

Advanced search

Quick links