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Functional & Integrative Genomics

, Volume 19, Issue 3, pp 487–496 | Cite as

The RNA-binding protein FXR1 modulates prostate cancer progression by regulating FBXO4

  • Hongwen Cao
  • Renjie Gao
  • Chao Yu
  • Lei ChenEmail author
  • Yigeng FengEmail author
Original Article

Abstract

This paper is to characterize the expression status of Fragile X Mental Retardation, Autosomal Homolog 1 (FXR1) in prostate cancer cells and understand its mechanistic involvement in the tumor biology of prostate cancer. The relative expression of FXR1 in prostate cancer cells was determined by real-time polymerase chain reaction and Western blotting. Cell proliferation in FXR1-deficient cells was evaluated by cell counting and MTT assays. The migrative and invasive capacities were measured by transwell assay. The potential regulatory effect of FXR1 on FBXO4 was interrogated using luciferase reporter assay. The direct bind of FXR1 with FBXO4 transcripts was analyzed by RNA immunoprecipitation and RNA pull-down assay. We observed aberrant overexpression of FXR1 in prostate cancer cells at both transcript and protein levels. FXR1 deficiency was associated with inhibited cell proliferation/viability and compromised migration/invasion in prostate cancer cells. Mechanistically, FXR1 negatively regulated FBXO4 transcripts via direct association with its 3′UTR and promoted mRNA degradation. FBXO4 knockdown predominantly rescued the tumor-suppressive phenotype in FXR1-deficient cells. We uncovered the oncogenic role of FXR1 in prostate cancer cells and further demonstrated its dependence on FBXO4. Our data highlight the importance of FXR1-FBXO4 signaling in prostate cancer.

Keywords

FXR1 FBXO4 Prostate cancer Migration Stability 

Notes

Acknowledgements

None.

Funding

This study was supported by The third batch of young Chinese name training program of LongHua Hospital Shanghai University of Traditional Chinese Medicine (Chen Lei, RC-2017-01-14); Shanghai Municipal Health and Family Planning Commission special subject of Chinese medicine research (2016JP014); National TCM clinical research base dragon medicine scholars (nursery plan) of LONGHUA Hospital Shanghai University of Traditional Chinese Medicine (LYTD-56); Shanghai School of Traditional Chinese Medicine Shanghai Inheritance Talents Training Project (LPRC-2017-015).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Not applicable.

References

  1. Catalona WJ (2018) Prostate cancer screening. Med Clin North Am 102:199–214.  https://doi.org/10.1016/j.mcna.2017.11.001 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Comtesse N, Keller A, Diesinger I, Bauer C, Kayser K, Huwer H, Lenhof HP, Meese E (2007) Frequent overexpression of the genes FXR1, CLAPM1 and EIF4G located on amplicon 3q26-27 in squamous cell carcinoma of the lung. Int J Cancer 120:2538–2544.  https://doi.org/10.1002/ijc.22585 CrossRefPubMedGoogle Scholar
  3. Demirci H, Reed D, Elner VM (2013) Tissue-based microarray expression of genes predictive of metastasis in uveal melanoma and differentially expressed in metastatic uveal melanoma. J Ophthalmic Vis Res 8:303–307PubMedPubMedCentralGoogle Scholar
  4. Fan Y, Yue J, Xiao M, Han-Zhang H, Wang YV, Ma C, Deng Z, Li Y, Yu Y, Wang X, Niu S, Hua Y, Weng Z, Atadja P, Li E, Xiang B (2017) FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion. Elife 6.  https://doi.org/10.7554/eLife.26129
  5. Feng C, Yang F, Wang J (2017) FBXO4 inhibits lung cancer cell survival by targeting Mcl-1 for degradation. Cancer Gene Ther 24:342–347.  https://doi.org/10.1038/cgt.2017.24 CrossRefPubMedGoogle Scholar
  6. Glass AS, Cary KC, Cooperberg MR (2013) Risk-based prostate cancer screening: who and how? Curr Urol Rep 14:192–198.  https://doi.org/10.1007/s11934-013-0319-8 CrossRefPubMedGoogle Scholar
  7. Hoffman RM (2011) Clinical practice. Screening for prostate cancer. N Engl J Med 365:2013–2019.  https://doi.org/10.1056/NEJMcp1103642 CrossRefPubMedGoogle Scholar
  8. Jin X, Zhai B, Fang T, Guo X, Xu L (2016) FXR1 is elevated in colorectal cancer and acts as an oncogene. Tumour Biol 37:2683–2690.  https://doi.org/10.1007/s13277-015-4068-9 CrossRefPubMedGoogle Scholar
  9. Lee EK, Lian Z, D’Andrea K, Letrero R, Sheng W, Liu S, Diehl JN, Pytel D, Barbash O, Schuchter L, Amaravaradi R, Xu X, Herlyn M, Nathanson KL, Diehl JA (2013) The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma. Mol Cell Biol 33:4422–4433.  https://doi.org/10.1128/MCB.00706-13 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Li Y, Hao B (2010) Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase. J Biol Chem 285:13896–13906.  https://doi.org/10.1074/jbc.M110.111518 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Lian Z, Lee EK, Bass AJ, Wong KK, Klein-Szanto AJ, Rustgi AK, Diehl JA (2015) FBXO4 loss facilitates carcinogen induced papilloma development in mice. Cancer Biol Ther 16:750–755.  https://doi.org/10.1080/15384047.2015.1026512 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Majumder M, House R, Palanisamy N, Qie S, Day TA, Neskey D, Diehl JA, Palanisamy V (2016) RNA-binding protein FXR1 regulates p21 and TERC RNA to bypass p53-mediated cellular senescence in OSCC. PLoS Genet 12:e1006306.  https://doi.org/10.1371/journal.pgen.1006306 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Mazroui R, Huot ME, Tremblay S, Boilard N, Labelle Y, Khandjian EW (2003) Fragile X mental retardation protein determinants required for its association with polyribosomal mRNPs. Hum Mol Genet 12:3087–3096.  https://doi.org/10.1093/hmg/ddg335 CrossRefPubMedGoogle Scholar
  14. Qian J, Hassanein M, Hoeksema MD, Harris BK, Zou Y, Chen H, Lu P, Eisenberg R, Wang J, Espinosa A, Ji X, Harris FT, Rahman SM, Massion PP (2015) The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers. Proc Natl Acad Sci U S A 112:3469–3474.  https://doi.org/10.1073/pnas.1421975112 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Qian J, Chen H, Ji X, Eisenberg R, Chakravarthy AB, Mayer IA, Massion PP (2017) A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy. Sci Rep 7:45828.  https://doi.org/10.1038/srep45828 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Qie S, Majumder M, Mackiewicz K, Howley BV, Peterson YK, Howe PH, Palanisamy V, Diehl JA (2017) Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma. Nat Commun 8:1534.  https://doi.org/10.1038/s41467-017-01199-8 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Schenck A, Bardoni B, Moro A, Bagni C, Mandel JL (2001) A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc Natl Acad Sci U S A 98:8844–8849.  https://doi.org/10.1073/pnas.151231598 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30.  https://doi.org/10.3322/caac.21166 CrossRefGoogle Scholar
  19. Whitman SA, Cover C, Yu L, Nelson DL, Zarnescu DC, Gregorio CC (2011) Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle. Circ Res 109:262–271.  https://doi.org/10.1161/CIRCRESAHA.111.244244 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Yang C, Strobel P, Marx A, Hofmann I (2013) Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis. Virchows Arch 463:379–390.  https://doi.org/10.1007/s00428-013-1452-y CrossRefPubMedGoogle Scholar
  21. Zhao BB, Yang ZJ, Wang Q, Pan ZM, Zhang W, Li L (2017) [Clinical validation of multiple biomarkers suspension array technology for ovarian cancer]. Zhonghua Fu Chan Ke Za Zhi 52:11–19.  https://doi.org/10.3760/cma.j.issn.0529-567X.2017.01.005 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Surgical Department I (Urology Department)LONGHUA Hospital Shanghai University of Traditional Chinese MedicineShanghai CityChina

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