Skip to main content
SpringerLink
Log in

LncFALEC recruits ART5/PARP1 and promotes castration-resistant prostate cancer through enhancing PARP1-meditated self PARylation

  • Research
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are abnormal expression in various malignant tumors. Our previous research demonstrated that focally amplified long non-coding RNA (lncRNA) on chromosome 1 (FALEC) is an oncogenic lncRNA in prostate cancer (PCa). However, the role of FALEC in castration-resistant prostate cancer (CRPC) is poorly understood. In this study, we showed FALEC was upregulated in post-castration tissues and CRPC cells, and increased FALEC expression was associated with poor survival in post-castration PCa patients. RNA FISH demonstrated FALEC was translocated into nucleus in CRPC cells. RNA pulldown and followed Mass Spectrometry (MS) assay demonstrated FALEC directly interacted with PARP1 and loss of function assay showed FALEC depletion sensitized CRPC cells to castration treatment and restored NAD+. Specific PARP1 inhibitor AG14361 and NAD+ endogenous competitor NADP+ sensitized FALEC-deleted CRPC cells to castration treatment. FALEC increasing PARP1 meditated self PARylation through recruiting ART5 and down regulation of ART5 decreased CRPC cell viability and restored NAD+ through inhibiting PARP1meditated self PARylation in vitro. Furthermore, ART5 was indispensable for FALEC directly interaction and regulation of PARP1, loss of ART5 impaired FALEC and PARP1 associated self PARylation. In vivo, FALEC depleted combined with PARP1 inhibitor decreased CRPC cell derived tumor growth and metastasis in a model of castration treatment NOD/SCID mice. Together, these results established that FALEC may be a novel diagnostic marker for PCa progression and provides a potential new therapeutic strategy to target the FALEC/ART5/PARP1 complex in CRPC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

Please contact author for data requests.

Abbreviations

CRPC:

Castration-resistant prostate cancer

ADT:

Androgen deprivation therapy

FISH:

Fluorescence in situ hybridization

CCK8:

Cell counting kit-8

MS:

Mass spectrometry

PARP:

Poly ADP-ribose polymerase

ART5:

ADP-Ribosyltransferase 5

FALEC :

Focally amplified lncRNA on chromosome 1

NAD:

Nicotinamide adenine dinucleotide

HR:

Homologous recombination

DDR:

DNA damage repair

AR:

Androgen receptor

BCA:

Bicinchoninic acid

RIP:

RNA binding protein immunoprecipitation

References

  1. R.L. Siegel, K.D. Miller, J. Ahmedin, Cancer statistics, 2015. Ca A Cancer Journal for Clinicians 60(5), 277–300 (2010)

    PubMed  Google Scholar 

  2. Y.N.S. Wong et al., Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat. Reviews Clin. Oncol. 11(6), 365–376 (2014)

    Article  CAS  Google Scholar 

  3. A. Mathur et al., Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells. Plos One 9(8), e103109 (2014)

    Article  Google Scholar 

  4. A. Katzenwadel, P. Wolf, Androgen deprivation of prostate cancer: leading to a therapeutic dead end. Cancer Lett 367(1), 12–17 (2015)

    Article  CAS  PubMed  Google Scholar 

  5. D.A. Gewirtz, S.E. Holt, L.W. Elmore, Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem. Pharmacol 76(8), 947–957 (2008)

    Article  CAS  PubMed  Google Scholar 

  6. A.V. D’Amico et al., Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. Jama 2008(3), 289–295 (2008)

    Google Scholar 

  7. M.D. Mason et al., Final report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus androgen-deprivation therapy alone in locally advanced prostate Cancer. J. Clin. Oncol 33(19), 2143–2150 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  8. C. Lin et al., Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139(6), 1069–1083 (2009)

    Article  Google Scholar 

  9. M.J. Schiewer et al., Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov 2(12), 1134 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. M. Asim et al., Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat. Commun. 8(1), 374 (2017)

  11. D. D'Amours et al., Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J. 342, 249-268 (1999)

  12.  O. Huambachano et al., Double-stranded DNA binding domain of poly(ADP-ribose) polymerase-1 and molecular insight into the regulation of its activity. J. Biol. Chem 286(9), 7149 (2011)

    Article  Google Scholar 

  13. J.P. Gagné et al., Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res. 36(22), 6959–6976 (2008)

    Article  Google Scholar 

  14. S. Jungmichel et al., Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses. Mol. Cell 52(2), 272–285 (2013)

    Article  CAS  PubMed  Google Scholar 

  15. C.J. Lord, A.N.J. Tutt, A. Ashworth, Synthetic lethality and Cancer therapy: Lessons learned from the development of PARP inhibitors. Annu. Rev. Med 66(1), 455–470 (2015)

    Article  CAS  PubMed  Google Scholar 

  16. J.M. Rodríguez-Vargas, F.J. Oliver-Pozo, F. Dantzer, PARP1 and Poly(ADP-ribosyl)ation signaling during autophagy in response to nutrient deprivation. Oxid. Med. Cell. Longev., 2641712 (2019)

  17. T. Ogura et al., Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells. Int. J. Oncol 48(6), 2330–2338 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. U. Igor, D.P. Bartel, lincRNAs: genomics, evolution, and mechanisms. Cell 154(1), 26–46 (2013)

    Article  Google Scholar 

  19. P. Batista, H. Chang, Long noncoding RNAs: Cellular address Codes in Development and Disease. Cell 152(6), 1298–1307 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. T.R. Mercer, M.E. Dinger, J.S. Mattick, Long non-coding RNAs: insights into functions. Nat. Rev. Genet 10(3), 155–159 (2009)

    Article  CAS  PubMed  Google Scholar 

  21. L. Qu et al., Exosome-transmitted lncARSR promotes Sunitinib Resistance in Renal Cancer by acting as a competing endogenous RNA. Cancer Cell. 29(5), 653–668 (2016)

    Article  CAS  PubMed  Google Scholar 

  22. C.C. Sun et al., FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway. Genome Med. 12(1), 77 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. E. Lau et al., Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression. Genome Med. 12(1), 72 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. P. Gu et al., A novel AR translational regulator lncRNA LBCS inhibits castration resistance of prostate cancer. Mol. Cancer 18(1), 109 (2019)

    Article  Google Scholar 

  25. P. Gu et al., lncRNA HOXD-AS1 regulates proliferation and chemo-resistance of castration-resistant prostate Cancer via recruiting WDR5. Mol Ther. 25(8), 1959–1973 (2017)

  26. J. Luo et al., LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling. Nat. Commun. 10(1), 2571 (2019)

  27. J. Chen et al., TFAP2C-Activated MALAT1 Modulates the Chemoresistance of Docetaxel-Resistant Lung Adenocarcinoma Cells. Mol. Ther. Nucleic Acids 14, 567–582 (2019)

  28. J. Chen et al., Long noncoding RNA CCAT1 acts as an oncogene and promotes chemoresistance in docetaxel-resistant lung adenocarcinoma cells. Oncotarget 7(38), 62474–62489 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  29. P. Huang et al., lncRNA profile study reveals the mRNAs and lncRNAs associated with docetaxel resistance in breast cancer cells. Sci. Rep 8(1), 17970 (2018)

    Article  Google Scholar 

  30. R. Zhao et al., Upregulation of the long non-coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients. Prostate 77(10), 1107–1117 (2017)

    Article  CAS  PubMed  Google Scholar 

  31. D. Liu et al., SIX1 promotes tumor lymphangiogenesis by coordinating TGFβ signals that increase expression of VEGF-C. Cancer Res 74(19), 5597–5607 (2014)

    Article  Google Scholar 

  32. W.R. Polkinghorn et al., Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 3(11), 1245–1253 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. M. Asim et al., Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat. Commun 8(1), 374 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  34. B.D. Cook et al., Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol. Cell. Biol. 22(1), 332-342 (2002)

  35. Y. Wu, M. Fabritius, C. Ip, Chemotherapeutic sensitization by endoplasmic reticulum stress: increasing the efficacy of taxane against prostate cancer. Cancer Biol. Ther 8(2), 146–152 (2009)

    Article  Google Scholar 

  36. M. Seman et al., Ecto-ADP-ribosyltransferases (ARTs): emerging actors in cell communication and signaling. Curr. Med. Chem 11(7), 857-872 (2004)

    PubMed  Google Scholar 

  37. C. Bourgeois et al., Identification of regulatory domains in ADP-ribosyltransferase-1 that determine transferase and NAD glycohydrolase activities. J. Biol. Chem 278(29), 26351–26355 (2003)

    Article  Google Scholar 

  38. M. Rouleau et al., PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer 10(4), 293–301 (2010)

    Article  Google Scholar 

  39. J. Murai et al., Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Eur. J. Cancer 48(21), 87–87 (2012)

    Google Scholar 

  40. C. Bian et al., NADP + is an Endogenous PARP Inhibitor in DNA Damage Response and Tumor Suppression. Nat. Commun. 10(1), 693

  41. Y. Cui et al., Acinar with ductal and mucinous adenocarcinoma of prostate cancer complicated with lung metastasis: a case report and literature review. Ann. Palliat. Med. 10(2), 2366–2370 (2021)

    Article  PubMed  Google Scholar 

  42. G.E. Polistina et al., Cavitary lung metastasis as relapse of prostate cancer. Respir Med. Case Rep. 29, 100973 (2020)

    CAS  PubMed  Google Scholar 

  43. T. Gutschner, S. Diederichs, The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6), 703–719 (2012)

    Article  Google Scholar 

  44. Y. Tang et al., LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis. Mol. Cancer 17(1), 77 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  45. M.C. Tsai et al., Long noncoding RNA as modular scaffold of histone modification complexes. Science 329(5992), 689–693 (2010)

    Article  Google Scholar 

  46. J. Jia et al., Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3. Oncotarget 7(25), 37868–37881 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  47. Z. Zhang et al., Regulation of androgen receptor splice variant AR3 by PCGEM1. Oncotarget 7(13), 15481–15491 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  48. K. Takayama et al., Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J 32(12), 1665–1680 (2014)

    Google Scholar 

  49. H.Q. Ta et al., Discovery of a novel long noncoding RNA overlapping the LCK gene that regulates prostate cancer cell growth. Mol. Cancer 18(1), 113 (2019)

    Article  Google Scholar 

  50. C.J. Ryan et al., Androgen Decline and Survival During Docetaxel Therapy in Metastatic Castration Resistant Prostate cancer (mCRPC). Prostate Cancer and Prostatic Dis. 23(1), 66-73 (2020)

  51. E. Fouquerel, R.W. Sobol, ARTD1 (PARP1) activation and NAD + in DNA repair and cell death. Dna Repair. 23, 27–32 (2014)

    Article  CAS  PubMed  Google Scholar 

  52. A.G. Baltz et al., The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell. 46(5), 674–690 (2012)

    Article  CAS  PubMed  Google Scholar 

  53. A. Castello et al., Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149(6), 1393–1406 (2012)

    Article  CAS  PubMed  Google Scholar 

  54. S. Geisler, J. Coller, RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mol. Cell. Biol. 14(11), 699–712 (2013 Nov)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Fei Shi, Lei Wu, and Di Cui contributed equally to this work.

Funding

This study was supported in part by grants from the Youth Fund Project of the National Natural Science Foundation (#81602252), the “Chen Guang” project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (#16CG10) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (#KYCX22_1836).

Author information

Authors and Affiliations

  1. Department of Urology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China

    Fei Shi, Di Cui, Menghao Sun, Zheng Deng, Bangmin Han, Shujie Xia & Feng Sun

  2. Department of Urology, Shanghai General Hospital, Nanjing Medical University, Shanghai, 200080, China

    Lei Wu, Zheng Zhou & Shujie Xia

  3. School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China

    Yuanhao Shen

  4. Institute of Urology, Shanghai Jiao Tong University, Shanghai, 200080, China

    Di Cui, Bangmin Han, Shujie Xia & Feng Sun

  5. Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, CA, 95817, USA

    Zheng Zhu

Authors
  1. Fei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Di Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Menghao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuanhao Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zheng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zheng Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bangmin Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shujie Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zheng Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Feng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study design: Feng Sun, Fei Shi, Zheng Zhu, Shujie Xia, Bangmin Han; Data collection: Fei Shi, Lei Wu, Zheng Zhou, Di Cui; Data analysis: Lei Wu, Menghao Sun, Zheng Zhu, Zheng Deng; Manuscript preparation: Fei Shi, Menghao Sun, Di Cui. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Zheng Zhu or Feng Sun.

Ethics declarations

Ethics approval and consent to participate

All experiments and procedures in the research involving human participants are in accordance with the ethical standards of the Research Ethics Committee of the Shanghai General Hospital. Informed consents have been acquired. Animal research has been approved and carried out strictly following the institutional ethical guidelines of the Committee on the Use of Live Animals of Shanghai General Hospital.

Disclosure Statement

We have no competing interests.

Additional information

Publisher’s Note

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

#Fei Shi, Lei Wu and Di Cui contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

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

Shi, F., Wu, L., Cui, D. et al. LncFALEC recruits ART5/PARP1 and promotes castration-resistant prostate cancer through enhancing PARP1-meditated self PARylation. Cell Oncol. 46, 761–776 (2023). https://doi.org/10.1007/s13402-023-00783-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-023-00783-z

Keywords

Search

Navigation