Skip to main content

Advertisement

SpringerLink
Log in

ZNFX1 anti-sense RNA 1 promotes the tumorigenesis of prostate cancer by regulating c-Myc expression via a regulatory network of competing endogenous RNAs

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

ZNFX1 anti-sense RNA 1 (ZFAS1) has been indicated in the tumorigenesis of various human cancers. However, the role of ZFAS1 in prostate cancer (PCa) progression and the underlying mechanisms remain incompletely understood. In the present study, we discovered that ZFAS1 is upregulated in PCa and that ZFAS1 overexpression predicted poor clinical outcomes. ZFAS1 overexpression notably promoted the proliferation, invasion, and epithelial–mesenchymal transition of PCa cells. Furthermore, we not only discovered that miR-27a/15a/16 are targeted by ZFAS1, which binds to their miRNA-response elements, but also revealed their tumor suppressor roles in PCa. We also identified that the Hippo pathway transducer YAP1, as well as its cooperator, TEAD1, are common downstream targets of miR-27a/15a/16. In addition, H3K9 demethylase KDM3A was found to be another target gene of miR-27a. Importantly, YAP1, TEAD1, and KDM3A all act as strong c-Myc inducers in an androgen-independent manner. Taken together, we suggest a regulatory network in which ZFAS1 is capable of enhancing c-Myc expression by inducing the expression of YAP1, TEAD1, and KDM3A through crosstalk with their upstream miRNAs, thereby globally promoting prostate cancer tumorigenesis.

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
Fig. 8

Similar content being viewed by others

Abbreviations

ZFAS1:

ZNFX1 anti-sense RNA 1

YAP1:

Yes-associated protein 1

TEAD1:

TEA domain transcription factor 1

KDM3A:

Lysine demethylase 3A

PCa:

Prostate cancer

ceRNA:

Competing endogenous RNA

AR:

Androgen receptor

PSA:

Prostate-specific antigen

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  PubMed  Google Scholar 

  2. Barry MJ, Simmons LH (2017) Prevention of prostate cancer morbidity and mortality: primary prevention and early detection. Med Clin North Am 101(4):787–806

    PubMed  Google Scholar 

  3. Robinson D, Van Allen EM, Wu YM et al (2015) Integrative clinical genomics of advanced prostate cancer. Cell 162(2):454

    CAS  PubMed  Google Scholar 

  4. Mitsiades N (2013) A road map to comprehensive androgen receptor axis targeting for castration-resistant prostate cancer. Cancer Res 73(15):4599–4605

    CAS  PubMed  Google Scholar 

  5. Sharma NL, Massie CE, Ramos-Montoya A et al (2013) The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 23(1):35–47

    CAS  PubMed  Google Scholar 

  6. Tsai MC, Spitale RC, Chang HY (2011) Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res 71(1):3–7

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ulitsky I, Bartel DP (2013) lincRNAs: genomics, evolution, and mechanisms. Cell 154(1):26–46

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang K, Liu CY, Zhou LY et al (2015) APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun 6:6779

    CAS  PubMed  Google Scholar 

  9. Xue X, Yang YA, Zhang A et al (2016) LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene 35(21):2746–2755

    CAS  PubMed  Google Scholar 

  10. Sun M, Nie F, Wang Y et al (2016) LncRNA HOXA11-AS Promotes Proliferation and Invasion of Gastric Cancer by Scaffolding the Chromatin Modification Factors PRC2, LSD1, and DNMT1. Cancer Res 76(21):6299–6310

    Article  CAS  PubMed  Google Scholar 

  11. Xue M, Chen W, Xiang A et al (2017) Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer 16(1):143

    PubMed  PubMed Central  Google Scholar 

  12. Wang H, Huo X, Yang XR et al (2017) STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Mol Cancer 16(1):136

    PubMed  PubMed Central  Google Scholar 

  13. Du Z, Sun T, Hacisuleyman E et al (2016) Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat Commun 7:10982

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Karreth FA, Reschke M, Ruocco A et al (2015) The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell 161(2):319–332

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Tay Y, Kats L, Salmena L et al (2011) Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147(2):344–357

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Song YX, Sun JX, Zhao JH et al (2017) Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion. Nat Commun 8(1):289

    PubMed  PubMed Central  Google Scholar 

  17. Ding J, Yeh CR, Sun Y et al (2018) Estrogen receptor β promotes renal cell carcinoma progression via regulating LncRNA HOTAIR-miR-138/200c/204/217 associated CeRNA network. Oncogene 37(37):5037–5053

    CAS  PubMed  Google Scholar 

  18. Chakravarty D, Sboner A, Nair SS et al (2014) The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat Commun 5:5383

    CAS  PubMed  Google Scholar 

  19. Zhang A, Zhao JC, Kim J et al (2015) LncRNA HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer. Cell Rep 13(1):209–221

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Askarian-Amiri ME, Crawford J, French JD et al (2011) SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer. RNA 17(5):878–891

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou H, Wang F, Chen H et al (2016) Increased expression of long-noncoding RNA ZFAS1 is associated with epithelial-mesenchymal transition of gastric cancer. Aging (Albany NY) 8(9):2023–2038

    CAS  Google Scholar 

  22. Li T, Xie J, Shen C et al (2015) Amplification of long noncoding RNA ZFAS1 promotes metastasis in hepatocellular carcinoma. Cancer Res 75(15):3181–3191

    CAS  PubMed  Google Scholar 

  23. Wang W, Xing C (2016) Upregulation of long noncoding RNA ZFAS1 predicts poor prognosis and prompts invasion and metastasis in colorectal cancer. Pathol Res Pract 212(8):690–695

    CAS  PubMed  Google Scholar 

  24. Liu R, Zeng Y, Zhou CF et al (2017) Long noncoding RNA expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients. Sci Rep 7(1):18

    PubMed  PubMed Central  Google Scholar 

  25. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hsieh AL, Walton ZE, Altman BJ, Stine ZE, Dang CV (2015) MYC and metabolism on the path to cancer. Semin Cell Dev Biol 43:11–21

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gil J, Kerai P, Lleonart M et al (2005) Immortalization of primary human prostate epithelial cells by c-Myc. Cancer Res 65(6):2179–2185

    CAS  PubMed  Google Scholar 

  28. Ellwood-Yen K, Graeber TG, Wongvipat J et al (2003) Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4(3):223–238

    CAS  PubMed  Google Scholar 

  29. Hubbard GK, Mutton LN, Khalili M et al (2016) Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res 76(2):283–292

    CAS  PubMed  Google Scholar 

  30. Xiang JF, Yin QF, Chen T et al (2014) Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res 24(5):513–531

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Xiao ZD, Han L, Lee H et al (2017) Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nat Commun 8(1):783

    PubMed  PubMed Central  Google Scholar 

  32. Fan L, Peng G, Sahgal N et al (2016) Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival. Oncogene 35(19):2441–2452

    CAS  PubMed  Google Scholar 

  33. Chandrashekar DS, Bashel B, Sah B et al (2017) UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19(8):649–658

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Paraskevopoulou MD, Vlachos IS, Karagkouni D et al (2016) DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts. Nucleic Acids Res 44(D1):D231–D238

    CAS  PubMed  Google Scholar 

  35. Vlachos IS, Zagganas K, Paraskevopoulou MD et al (2015) DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res 43(1):460–466

    Google Scholar 

  36. Pan D (2010) The hippo signaling pathway in development and cancer. Dev Cell 19(4):491–505

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zanconato F, Cordenonsi M, Piccolo S (2016) YAP/TAZ at the roots of cancer. Cancer Cell 29(6):783–803

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Moroishi T, Hansen CG, Guan KL (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15(2):73–79

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bonci D, Coppola V, Musumeci M et al (2008) The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14(11):1271–1277

    CAS  PubMed  Google Scholar 

  40. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120(1):15–20

    CAS  PubMed  Google Scholar 

  41. Liu-Chittenden Y, Huang B, Shim JS et al (2012) Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26(12):1300–1305

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Koontz LM, Liu-Chittenden Y, Yin F et al (2013) The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell 25(4):388–401

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Santucci M, Vignudelli T, Ferrari S et al (2015) The hippo pathway and YAP/TAZ-TEAD protein–protein interaction as targets for regenerative medicine and cancer treatment. J Med Chem 58(12):4857–4873

    CAS  PubMed  Google Scholar 

  44. Jiao S, Wang H, Shi Z et al (2014) A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25(2):166–180

    CAS  PubMed  Google Scholar 

  45. Wang Z, Wu Y, Wang H et al (2014) Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci USA 111(1):E89–E98

    CAS  PubMed  Google Scholar 

  46. Wang L, Shi S, Guo Z et al (2013) Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS One 8(6):e65539

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Goda S, Isagawa T, Chikaoka Y, Kawamura T, Aburatani H (2013) Control of histone H3 lysine 9 (H3K9) methylation state via cooperative two-step demethylation by Jumonji domain containing 1A (JMJD1A) homodimer. J Biol Chem 288(52):36948–36956

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gurel B, Iwata T, Koh CM et al (2008) Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol 21(9):1156–1167

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Koh CM, Bieberich CJ, Dang CV, Nelson WG, Yegnasubramanian S, De Marzo AM (2010) MYC and prostate cancer. Genes Cancer 1(6):617–628

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Cho H, Herzka T, Zheng W et al (2014) RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis. Cancer Discov 4(3):318–333

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang J, Kobayashi T, Floc’h N et al (2012) B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. Cancer Res 72(18):4765–4776

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kim J, Roh M, Doubinskaia I, Algarroba GN, Eltoum IE, Abdulkadir SA (2012) A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. Oncogene 31(3):322–332

    CAS  PubMed  Google Scholar 

  53. Zhang P, Cao L, Fan P, Mei Y, Wu M (2016) LncRNA-MIF, a c-Myc-activated long non-coding RNA, suppresses glycolysis by promoting Fbxw7-mediated c-Myc degradation. EMBO Rep 17(8):1204–1220

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kawasaki Y, Komiya M, Matsumura K et al (2016) MYU, a target lncRNA for Wnt/c-Myc signaling, mediates induction of CDK6 to promote cell cycle progression. Cell Rep 16(10):2554–2564

    CAS  PubMed  Google Scholar 

  55. Chen X, Yang C, Xie S, Cheung E (2018) Long non-coding RNA GAS5 and ZFAS1 are prognostic markers involved in translation targeted by miR-940 in prostate cancer. Oncotarget 9:1048–1062

    PubMed  Google Scholar 

  56. Aqeilan RI, Calin GA, Croce CM (2010) miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ 17(2):215–220

    CAS  PubMed  Google Scholar 

  57. Bonci D, Coppola V, Patrizii M et al (2016) A microRNA code for prostate cancer metastasis. Oncogene 35(9):1180–1192

    CAS  PubMed  Google Scholar 

  58. Chang TC, Yu D, Lee YS et al (2008) Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40(1):43–50

    CAS  PubMed  Google Scholar 

  59. Xue G, Yan HL, Zhang Y et al (2015) c-Myc-mediated repression of miR-15-16 in hypoxia is induced by increased HIF-2α and promotes tumor angiogenesis and metastasis by upregulating FGF2. Oncogene 34(11):1393–1406

    CAS  PubMed  Google Scholar 

  60. Tang W, Yu F, Yao H et al (2014) miR-27a regulates endothelial differentiation of breast cancer stem like cells. Oncogene 33(20):2629–2638

    CAS  PubMed  Google Scholar 

  61. Colangelo T, Polcaro G, Ziccardi P et al (2016) The miR-27a-calreticulin axis affects drug-induced immunogenic cell death in human colorectal cancer cells. Cell Death Dis 7:e2108

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Sun Y, Yang X, Liu M, Tang H (2016) B4GALT3 up-regulation by miR-27a contributes to the oncogenic activity in human cervical cancer cells. Cancer Lett 375(2):284–292

    CAS  PubMed  Google Scholar 

  63. Fletcher CE, Dart DA, Sita-Lumsden A, Cheng H, Rennie PS, Bevan CL (2012) Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer. Hum Mol Genet 21(14):3112–3127

    CAS  PubMed  Google Scholar 

  64. Mo W, Zhang J, Li X et al (2013) Identification of novel AR-targeted microRNAs mediating androgen signalling through critical pathways to regulate cell viability in prostate cancer. PLoS One 8(2):e56592

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wan X, Huang W, Yang S et al (2016) Androgen-induced miR-27A acted as a tumor suppressor by targeting MAP2K4 and mediated prostate cancer progression. Int J Biochem Cell Biol 79:249–260

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by grant from the National Natural Science Foundation of China (Grant No. 81702505). The funding bodies played no role in the design or interpretation of the study.

Author information

Authors and Affiliations

  1. Department of Urology, First Hospital of China Medical University, Shenyang, 110001, China

    Xiaolu Cui, Chiyuan Piao, Zhe Zhang & Xiankui Liu

  2. Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, 110042, China

    Chengcheng Lv

  3. Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, 110001, China

    Xuyong Lin

Authors
  1. Xiaolu Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiyuan Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chengcheng Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuyong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhe Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiankui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XC and CP conceived and designed the study. XC and CP performed the experiments. XC and CL analyzed the data and prepared the manuscript. ZZ and X Liu contributed the experimental reagents and materials. X Lin did the pathological diagnosis and provided the pathological sections. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Xiankui Liu.

Additional information

Publisher's Note

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

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, X., Piao, C., Lv, C. et al. ZNFX1 anti-sense RNA 1 promotes the tumorigenesis of prostate cancer by regulating c-Myc expression via a regulatory network of competing endogenous RNAs. Cell. Mol. Life Sci. 77, 1135–1152 (2020). https://doi.org/10.1007/s00018-019-03226-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-019-03226-x

Keywords

Search

Navigation