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.

  • Original Article
  • Published:

Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer

Oncogene volume 34, pages 2094–2102 (2015)Cite this article

Subjects

Abstract

Overwhelming evidence indicates that cancer is a genetic disease caused by the accumulation of mutations in oncogenes and tumor suppressor genes. It is also increasingly apparent, however, that cancer depends not only on mutations in these coding genes but also on alterations in the large class of non-coding RNAs. Here, we report that one such long non-coding RNA, TRPM2-AS, an antisense transcript of TRPM2, which encodes an oxidative stress-activated ion channel, is overexpressed in prostate cancer (PCa). The high expression of TRPM2-AS and its related gene signature were found to be linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Mechanistically, TRPM2-AS knockdown led to PCa cell apoptosis, with a transcriptional profile that indicated an unbearable increase in cellular stress in the dying cells, which was coupled to cell cycle arrest, an increase in intracellular hydrogen peroxide and activation of the sense TRPM2 gene. Moreover, targets of existing drugs and treatments were found to be consistently associated with high TRPM2-AS levels in both targeted cells and patients, ultimately suggesting that the measurement of the expression levels of TRPM2-AS allows not only for the early identification of aggressive PCa tumors, but also identifies a subset of at-risk patients who would benefit from currently available, but mostly differently purposed, therapeutic agents.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Johansson JE, Andrén O, Andersson SO, Dickman PW, Holmberg L, Magnuson A et al. Natural history of early, localized prostate cancer. JAMA 2004; 291: 2713–2719.

    Article  CAS  Google Scholar 

  2. Lu-Yao GL, Albertsen PC, Moore DF, Shih W, Lin Y, DiPaola RS et al. Outcomes of localized prostate cancer following conservative management. JAMA 2009; 302: 1202–1209.

    Article  CAS  Google Scholar 

  3. Stark JR, Mucci L, Rothman KJ, Adami HO . Screening for prostate cancer remains controversial. BMJ 2009; 339: b3601.

    Article  Google Scholar 

  4. Schröder FH . Landmarks in prostate cancer screening. BJU Int 2012; 1: 3–7.

    Article  Google Scholar 

  5. Xia J, Gulati R, Au M, Gore JL, Lin DW, Etzioni R . Effects of screening on radical prostatectomy efficacy: the prostate cancer intervention versus observation trial. J Natl Cancer Inst 2013; 105: 546–550.

    Article  Google Scholar 

  6. Mattick JS . RNA regulation: a new genetics? Nat Rev Genet 2004; 5: 316–323.

    Article  CAS  Google Scholar 

  7. Prasanth KV, Spector DL . Eukaryotic regulatory RNAs: an answer to the 'genome complexity' conundrum. Genes Dev 2007; 21: 11–42.

    Article  CAS  Google Scholar 

  8. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 2011; 477: 295–300.

    Article  CAS  Google Scholar 

  9. Kretz M, Siprashvili Z, Chu C, Webster DE, Zehnder A, Qu K et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 2013; 493: 231–235.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010; 464: 1071–1076.

    Article  CAS  Google Scholar 

  12. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res 2011; 71: 6320–6326.

    Article  CAS  Google Scholar 

  13. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 2013; 32: 1616–1625.

    Article  CAS  Google Scholar 

  14. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol 2011; 29: 742–749.

    Article  CAS  Google Scholar 

  15. Orfanelli U, Wenke AK, Doglioni C, Russo V, Bosserhoff AK, Lavorgna G . Identification of novel sense and antisense transcription at the TRPM2 locus in cancer. Cell Res 2008; 18: 1128–1140.

    Article  CAS  Google Scholar 

  16. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11–22.

    Article  CAS  Google Scholar 

  17. Draghici S, Khatri P, Eklund AC, Szallasi Z . Reliability and reproducibility issues in DNA microarray measurements. Trends Genet 2006; 22: 101–109.

    Article  CAS  Google Scholar 

  18. Petrovics G, Liu A, Shaheduzzaman S, Furusato B, Sun C, Chen Y et al. Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 2005; 24: 3847–3852.

    Article  CAS  Google Scholar 

  19. Ribeiro F, Paulo P, Costa VL, Barros-Silva JD, Ramalho-Carvalho J, Jerónimo C et al. Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene. PLoS ONE 2011; 6: e22317.

    Article  CAS  Google Scholar 

  20. Brase JC, Johannes M, Mannsperger H, Fälth M, Metzger J, Kacprzyk LA et al. TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling. BMC Cancer 2011; 11: 507.

    Article  CAS  Google Scholar 

  21. Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 2008; 10: 177–188.

    Article  CAS  Google Scholar 

  22. Sboner A, Demichelis F, Calza S, Pawitan Y, Setlur SR, Hoshida Y et al. Molecular sampling of prostate cancer: a dilemma for predicting disease progression. BMC Med Genomics 2010; 16: 3–8.

    Google Scholar 

  23. Glinsky GV, Glinskii AB, Stephenson AJ, Hoffman RM, Gerald WL . Gene expression profiling predicts clinical outcome of prostate cancer. J Clin Invest 2004; 113: 913–923.

    Article  CAS  Google Scholar 

  24. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  25. Wang G, Yang ZQ, Zhang K . Endoplasmic reticulum stress response in cancer: molecular mechanism and therapeutic potential. Am J Transl Res 2010; 2: 65–74.

    PubMed  Google Scholar 

  26. Bai JZ, Lipski J . Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stress-induced cell death in organotypic hippocampal culture. Neurotoxicology 2010; 31: 204–214.

    Article  CAS  Google Scholar 

  27. Di A, Gao XP, Qian F, Kawamura T, Han J, Hecquet C et al. The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. Nat Immunol 2011; 13: 29–34.

    Article  Google Scholar 

  28. Chen SJ, Zhang W, Tong Q, Conrad K, Hirschler-Laszkiewicz I, Bayerl M et al. Role of TRPM2 in cell proliferation and susceptibility to oxidative stress. Am J Physiol Cell Physiol 2013; 304: C548–C560.

    Article  CAS  Google Scholar 

  29. Miller BA . The role of TRP channels in oxidative stress-induced cell death. J Membr Biol 2006; 209: 31–41.

    Article  CAS  Google Scholar 

  30. Zhang W, Hirschler-Laszkiewicz I, Tong Q, Conrad K, Sun SC, Penn L et al. TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage. Am J Physiol Cell Physiol 2006; 29: C1146–C1159.

    Article  Google Scholar 

  31. Kaneko S, Kawakami S, Hara Y, Conrad K, Sun SC, Penn L et al. A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J Pharmacol Sci 2006; 101: 66–76.

    Article  CAS  Google Scholar 

  32. Ishii M, Oyama A, Hagiwara T, Miyazaki A, Mori Y, Kiuchi Y et al. Facilitation of H2O2-induced A172 human glioblastoma cell death by insertion of oxidative stress-sensitive TRPM2 channels. Anticancer Res 2007; 27: 3987–3992.

    CAS  PubMed  Google Scholar 

  33. Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T, Hara Y et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med 2008; 14: 738–747.

    Article  CAS  Google Scholar 

  34. Verma S, Quillinan N, Yang YF, Nakayama S, Cheng J, Kelley MH et al. TRPM2 channel activation following in vitro ischemia contributes to male hippocampal cell death. Neurosci Lett 2012; 530: 41–46.

    Article  CAS  Google Scholar 

  35. Zeng X, Sikka SC, Huang L, Sun C, Xu C, Jia D et al. Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation. Prostate Cancer Prostatic Dis 2010; 13: 195–201.

    Article  CAS  Google Scholar 

  36. Lavorgna G, Dahary D, Lehner B, Sorek R, Sanderson CM, Casari G . In search of antisense. Trends Biochem Sci 2004; 29: 88–94.

    Article  CAS  Google Scholar 

  37. Cheville JC, Karnes RJ, Therneau TM, Helgeson BE, Cao X, Morris DS et al. Gene panel model predictive of outcome in men at high-risk of systemic progression and death from prostate cancer after radical retropubic prostatectomy. J Clin Oncol 2008; 26: 3930–3936.

    Article  Google Scholar 

  38. Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with PCa: a retrospective study. Lancet Oncol 2011; 12: 245–255.

    Article  CAS  Google Scholar 

  39. Penney KL, Sinnott JA, Fall K, Pawitan Y, Hoshida Y, Kraft P et al. mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol 2011; 29: 2391–2396.

    Article  CAS  Google Scholar 

  40. Markert EK, Mizuno H, Vazquez A, Levine AJ . Molecular classification of prostate cancer using curated expression signatures. Proc Natl Acad Sci USA 2011; 108: 21276–21281.

    Article  CAS  Google Scholar 

  41. Agell L, Hernández S, Nonell L, Lorenzo M, Puigdecanet E, de Muga et al. A 12-gene expression signature is associated with aggressive histological in prostate cancer: SEC14L1 and TCEB1 genes are potential markers of progression. Am J Pathol 2012; 18: 1585–1594.

    Article  Google Scholar 

  42. Gasi Tandefelt D, Boormans JL, van der Korput HA, Jenster GW, Trapman J . A 36-gene signature predicts clinical progression in a subgroup of ERG-positive PCas. Eur Urol 2013; 64: 941–950 pii: S0302-2838(13)00222-4.

    Article  CAS  Google Scholar 

  43. Irshad S, Bansal M, Castillo-Martin M, Zheng T, Aytes A, Wenske et al. A molecular signature predictive of indolent prostate cancer. Sci Transl Med 2013; 5: 202ra122.

    Article  Google Scholar 

  44. Barabási AL, Gulbahce N, Loscalzo J . Network medicine: a network-based approach to human disease. Nat Rev Genet 2011; 12: 56–68.

    Article  Google Scholar 

  45. US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research & Center for Biologics Evaluation and Research Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics (2007).

  46. Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 2011; 470: 269–273.

    Article  CAS  Google Scholar 

  47. Hessels D, Schalken JA . The use of PCA3 in the diagnosis of PCa. Nat Rev Urol 2009; 6: 255–261.

    Article  CAS  Google Scholar 

  48. Davidson BL, McCray PB. Jr Current prospects for RNA interference-based therapies. Nat Rev Genet 2011; 12: 329–340.

    Article  CAS  Google Scholar 

  49. Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012; 30: 453–459.

    Article  CAS  Google Scholar 

  50. Boyle EI, Weng S, Gollub J, Jin H, Botstein D, Cherry JM et al. GO::TermFinder–open source software for accessing gene ontology information and finding significantly enriched gene ontology terms associated with a list of genes. Bioinformatics 2004; 20: 3710–3715.

    Article  CAS  Google Scholar 

  51. Miller EW, Tulyanthan O, Isacoff EY, Chang CJ . Molecular imaging of hydrogen peroxide produced for cell signaling. Nat Chem Biol 2007; 3: 263–267.

    Article  CAS  Google Scholar 

  52. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B . Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008; 5: 621–628.

    Article  CAS  Google Scholar 

  53. Xing Y, Kapur K, Wong WH . Probe selection and expression index computation of Affymetrix Exon Arrays. PLoS ONE 2006; 1: e88.

    Article  Google Scholar 

  54. Simon RM, Paik S, Hayes DF . Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009; 101: 1446–1452.

    Article  Google Scholar 

  55. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008; 40: 499–507.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Alleanza Contro il Cancro (AACR) to GL, the Italian Ministry of Health to MB and the Associazione Italiana per la Ricerca sul Cancro (AIRC) to MB.

Author information

Author notes

  1. U Orfanelli

    Present address: 7Current address: San Raffaele Scientific Institute, Division of Genetics and Cell Biology and BoNetwork, DiBiT, Milan, Italy.,

Authors and Affiliations

  1. San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Milan, Italy

    U Orfanelli, G Casari & G Lavorgna

  2. San Raffaele Scientific Institute, Cellular Immunology Unit, Milan, Italy

    E Jachetti, M Grioni & M Bellone

  3. Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy

    F Chiacchiera & D Pasini

  4. Division of Neuroscience, San Raffaele Scientific Institute, Institute of Experimental Neurology (INSPE), Laboratory of Genetics of Neurological Complex Disorders, Milan, Italy

    P Brambilla & F Martinelli-Boneschi

  5. Vita-Salute San Raffaele University and Department of Urology, San Raffaele Scientific Institute, Milan, Italy

    A Briganti & F Montorsi

  6. Department of Pathology, Vita-Salute University San Raffaele, Milan, Italy

    M Freschi & C Doglioni

Authors
  1. U Orfanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Jachetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Chiacchiera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Grioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Brambilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Briganti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Freschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F Martinelli-Boneschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Doglioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Montorsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Bellone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G Casari
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Pasini
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. G Lavorgna
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M Bellone or G Lavorgna.

Ethics declarations

Competing interests

This work is the subject of a US provisional patent application.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Orfanelli, U., Jachetti, E., Chiacchiera, F. et al. Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene 34, 2094–2102 (2015). https://doi.org/10.1038/onc.2014.144

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.144

This article is cited by

Search

Advanced search

Quick links