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.

  • Article
  • Published:

miR-30 disrupts senescence and promotes cancer by targeting both p16INK4A and DNA damage pathways

Oncogene volume 37, pages 5618–5632 (2018)Cite this article

Subjects

Abstract

miR-30 is a microRNA frequently overexpressed in human cancers. However, the biological consequence of miR-30 overexpression in cancer has been unclear. In a genetic screen, miR-30 was found to abrogate oncogenic-induced senescence, a key tumor-suppressing mechanism that involves DNA damage responses, activation of p53 and induction of p16INK4A. In cells and mouse models, miR-30 disrupts senescence and promotes cancer by suppressing 2 targets, CHD7 and TNRC6A. We show that while CHD7 is a transcriptional coactivator essential for induction of p16INK4A in senescent cells, TNRC6A, a miRNA machinery component, is required for expression and functionality of DNA damage response RNAs (DDRNAs) that mediate DNA damage responses and p53 activation by orchestrating histone modifications, chromatin remodeling and recruitment of DNA damage factors at damaged sites. Thus, miR-30 inhibits both p16INK4A and p53, 2 key senescence effectors, leading to efficient senescence disruption. These findings have identified novel signaling pathways mediating oncogene-induced senescence and tumor-suppression, and revealed the molecular and cellular mechanisms underlying the oncogenic activity of miR-30. Thus, the miR-30/CHD7/TNRC6A pathway is potentially a novel diagnostic biomarker and therapeutic target for cancer.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fabbri M, Croce CM, Calin GA. MicroRNAs. Cancer J. 2008;14:1–6.

    Article  CAS  PubMed  Google Scholar 

  2. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Landthaler M, Gaidatzis D, Rothballer A, Chen PY, Soll SJ, Dinic L, et al. Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA. 2008;14:2580–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Courtois-Cox S, Jones SL, Cichowski K. Many roads lead to oncogene-induced senescence. Oncogene. 2008;27:2801–9.

    Article  CAS  PubMed  Google Scholar 

  5. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–7.

    Article  CAS  PubMed  Google Scholar 

  6. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444:638–42.

    Article  CAS  PubMed  Google Scholar 

  7. Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002;22:3389–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P. p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. J Biol Chem. 2009;284:11237–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kwong J, Chen M, Lv D, Luo N, Su W, Xiang R, et al. Induction of p38delta expression plays an essential role in oncogenic ras-induced senescence. Mol Cell Biol. 2013;33:3780–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22:3497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Narita M, Lowe SW. Senescence comes of age. Nat Med. 2005;11:920–2.

    Article  CAS  PubMed  Google Scholar 

  12. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128:295–308.

    Article  CAS  PubMed  Google Scholar 

  13. Zhao T, Li J, Chen AF. MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab. 2010;299:E110–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Faraonio R, Salerno P, Passaro F, Sedia C, Iaccio A, Bellelli R, et al. A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts. Cell Death Differ. 2011;19:713–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Srikantan S, Gorospe M, Abdelmohsen K. Senescence-associated microRNAs linked to tumorigenesis. Cell Cycle. 2011;10:3211–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hong L, Lai M, Chen M, Xie C, Liao R, Kang YJ, et al. The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene-induced senescence. Cancer Res. 2010;70:8547–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wei W, Ba Z, Gao M, Wu Y, Ma Y, Amiard S, et al. A role for small RNAs in DNA double-strand break repair. Cell. 2012;149:101–12.

    Article  CAS  PubMed  Google Scholar 

  18. Francia S, Michelini F, Saxena A, Tang D, de HM, Anelli V, et al. Site-specific DICER and DROSHA RNA products control the DNA-damage response. Nature. 2012;488:231–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang Q, Goldstein M. Small RNAs recruit chromatin-modifying enzymes MMSET and Tip60 to reconfigure damaged DNA upon double-strand break and facilitate repair. Cancer Res. 2016;76:1904–15.

    Article  CAS  PubMed  Google Scholar 

  20. Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell. 2007;131:146–59.

    Article  CAS  PubMed  Google Scholar 

  21. DiGiovanni J. Modification of multistage skin carcinogenesis in mice. Prog Exp Tumor Res. 1991;33:192–229.

    Article  CAS  PubMed  Google Scholar 

  22. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54:63–128.

    Article  CAS  PubMed  Google Scholar 

  23. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.

    Article  CAS  PubMed  Google Scholar 

  24. Caldwell ME, DeNicola GM, Martins CP, Jacobetz MA, Maitra A, Hruban RH, et al. Cellular features of senescence during the evolution of human and murine ductal pancreatic cancer. Oncogene. 2012;31:1599–608.

    Article  CAS  PubMed  Google Scholar 

  25. Flanagan JF, Mi LZ, Chruszcz M, Cymborowski M, Clines KL, Kim Y, et al. Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature. 2005;438:1181–5.

    Article  CAS  PubMed  Google Scholar 

  26. Schnetz MP, Bartels CF, Shastri K, Balasubramanian D, Zentner GE, Balaji R, et al. Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res. 2009;19:590–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schnetz MP, Handoko L, Akhtar-Zaidi B, Bartels CF, Pereira CF, Fisher AG, et al. CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression. PLoS Genet. 2010;6:e1001023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bajpai R, Chen DA, Rada-Iglesias A, Zhang J, Xiong Y, Helms J, et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature. 2010;463:958–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Engelen E, Akinci U, Bryne JC, Hou J, Gontan C, Moen M, et al. Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet. 2011;43:607–11.

    Article  CAS  PubMed  Google Scholar 

  30. Kim MS, Oh JE, Kim YR, Park SW, Kang MR, Kim SS, et al. Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers. J Pathol. 2010;221:139–46.

    Article  CAS  PubMed  Google Scholar 

  31. Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, et al. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009;325:965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kumar MS, Pester RE, Chen CY, Lane K, Chin C, Lu J, et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 2009;23:2700–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.

    Article  CAS  PubMed  Google Scholar 

  34. d’Adda di FF. A direct role for small non-coding RNAs in DNA damage response. Trends Cell Biol. 2014;24:171–8.

    Article  CAS  Google Scholar 

  35. Wang H, Shao Z, Shi LZ, Hwang PY, Truong LN, Berns MW, et al. CtIP protein dimerization is critical for its recruitment to chromosomal DNA double-stranded breaks. J Biol Chem. 2012;287:21471–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu Y, Ayrapetov MK, Xu C, Gursoy-Yuzugullu O, Hu Y, Price BD. Histone H2A.Z controls a critical chromatin remodeling step required for DNA double-strand break repair. Mol Cell. 2012;48:723–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Price BD, D’Andrea AD. Chromatin remodeling at DNA double-strand breaks. Cell. 2013;152:1344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Berkovich E, Monnat RJ Jr., Kastan MB. Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat Cell Biol. 2007;9:683–90.

    Article  CAS  PubMed  Google Scholar 

  39. Hurd EA, Capers PL, Blauwkamp MN, Adams ME, Raphael Y, Poucher HK, et al. Loss of Chd7 function in gene-trapped reporter mice is embryonic lethal and associated with severe defects in multiple developing tissues. Mamm Genome. 2007;18:94–104.

    Article  CAS  PubMed  Google Scholar 

  40. Jongmans MC, Admiraal RJ, van der Donk KP, Vissers LE, Baas AF, Kapusta L, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006;43:306–14.

    Article  CAS  PubMed  Google Scholar 

  41. Eystathioy T, Chan EK, Tenenbaum SA, Keene JD, Griffith K, Fritzler MJ. A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles. Mol Biol Cell. 2002;13:1338–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Luhrmann R, et al. Identification of novel argonaute-associated proteins. Curr Biol. 2005;15:2149–55.

    Article  CAS  PubMed  Google Scholar 

  43. Meister G. Argonaute proteins: functional insights and emerging roles. Nat Rev Genet. 2013;14:447–59.

    Article  CAS  PubMed  Google Scholar 

  44. Zamudio JR, Kelly TJ, Sharp PA. Argonaute-bound small RNAs from promoter-proximal RNA polymerase II. Cell. 2014;156:920–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sun P, Dong P, Dai K, Hannon GJ, Beach D. p53-independent role of MDM2 in TGF-beta1 resistance. Science. 1998;282:2270–2.

    Article  CAS  PubMed  Google Scholar 

  46. Zeng PY,Vakoc CR,Chen ZC,Blobel GA,Berger SL, In vivo dual cross-linking for identification of indirect DNA-associated proteins by chromatin immunoprecipitation. Biotechniques. 2006;41:694–6.

    Article  CAS  PubMed  Google Scholar 

  47. Mukhopadhyay A, Deplancke B, Walhout AJ, Tissenbaum HA. Chromatin immunoprecipitation (ChIP) coupled to detection by quantitative real-time PCR to study transcription factor binding to DNA in Caenorhabditis elegans. Nat Protoc. 2008;3:698–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gertsenstein M, Nutter LM, Reid T, Pereira M, Stanford WL, Rossant J, et al. Efficient generation of germ line transmitting chimeras from C57BL/6N ES cells by aggregation with outbred host embryos. PLoS ONE. 2010;5:e11260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yoshizuka N, Chen RM, Xu Z, Liao R, Hong L, Hu WY, et al. A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis. Mol Cell Biol. 2012;32:606–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Joanna Wysocka for CHD7 cDNA, and Tumor Tissue and Pathology, Biostatistics and Bioinformatics, Cell & Viral Vector Laboratory and Cellular Imaging Shared Resources of WFBCCC. This study was supported by Overseas Collaboration Fund from National NSF of China 31428013 (PS, RX), NIH/NCI grants CA106768, CA131231, CA172115 (PS), P30CA012197, and Thomas K. Hearn Brain Tumor Center. WS is supported by International Postdoctoral Exchange Fellowship Program by Office of China Postdoctoral Council (20140027).

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Weijun Su, Shan Huang, Denise Herpai, Wei Zhang, Waldemar Debinski & Peiqing Sun

  2. School of Medicine, Nankai University, Tianjin, China

    Weijun Su, Yingxi Xu & Rong Xiang

  3. Departments of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA

    Lixin Hong, Yingxi Xu, Lan Truong, Xiaohua Wu & Peiqing Sun

  4. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Lixin Hong, Lisheng Li & Jiahuai Han

  5. No 2 People’s Hospital of Wuxi City, Wuxi, China

    Xin Xu

  6. Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Denise Herpai & Waldemar Debinski

  7. Biosettia Inc, San Diego, CA, USA

    Wen-Yuan Hu

  8. Departments of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA

    Changchun Xiao

  9. Center for Cancer Genomics and Precision Oncology, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Wei Zhang

Authors
  1. Weijun Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lixin Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Denise Herpai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lisheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yingxi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lan Truong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wen-Yuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaohua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Changchun Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jiahuai Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Waldemar Debinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rong Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Peiqing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peiqing Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

These authors contribute equally: Weijun Su, Lixin Hong, Xin Xu.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, W., Hong, L., Xu, X. et al. miR-30 disrupts senescence and promotes cancer by targeting both p16INK4A and DNA damage pathways. Oncogene 37, 5618–5632 (2018). https://doi.org/10.1038/s41388-018-0358-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0358-1

This article is cited by

Search

Advanced search

Quick links