MINA controls proliferation and tumorigenesis of glioblastoma by epigenetically regulating cyclins and CDKs via H3K9me3 demethylation


It is generally known that histone demethylases regulate gene transcription by altering the methylate status on histones, but their roles in cancers and the underlying molecular mechanisms still remain unclear. MYC-induced nuclear antigen (MINA) is reported to be a histone demethylase and highly expressed in many cancers. Here, for the first time, we show that MINA is involved in glioblastoma carcinogenesis and reveal the probable mechanisms of it in cell-cycle control. Kaplan–Meier analysis of progression-free survival showed that high MINA expression was strongly correlated with poor outcome and advancing tumor stage. MINA knockdown significantly repressed the cell proliferation and tumorigenesis abilities of glioblastoma cells in vitro and in vivo that were rescued by overexpressing the full-length MINA afterwards. Microarray analysis after knockdown of MINA revealed that MINA probably regulated glioblastoma carcinogenesis through the predominant cell-cycle pathways. Further investigation showed that MINA deficiency led to a cell-cycle arrest in G1 and G2 phases. And among the downstream genes, we found that cyclins and cyclin-dependent kinases were directly activated by MINA via the demethylation of H3K9me3.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7


  1. 1

    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–996.

    CAS  Article  Google Scholar 

  2. 2

    Benjamin R, Capparella J, Brown A . Classification of glioblastoma multiforme in adults by molecular genetics. Cancer J 2003; 9: 82–90.

    CAS  Article  Google Scholar 

  3. 3

    Weller M, Cloughesy T, Perry JR, Wick W . Standards of care for treatment of recurrent glioblastoma—are we there yet? Neuro Oncol 2013; 15: 4–27.

    Article  Google Scholar 

  4. 4

    Xie Q, Mittal S, Berens ME . Targeting adaptive glioblastoma: an overview of proliferation and invasion. Neuro Oncol 2014; 16: 1575–1584.

    CAS  Article  Google Scholar 

  5. 5

    Tsuneoka M, Koda Y, Soejima M, Teye K, Kimura H . A novel myc target gene, mina53, that is involved in cell proliferation. J Biol Chem 2002; 277: 35450–35459.

    CAS  Article  Google Scholar 

  6. 6

    Zhang Y, Lu Y, Yuan BZ, Castranova V, Shi X, Stauffer JL et al. The Human mineral dust-induced gene, mdig, is a cell growth regulating gene associated with lung cancer. Oncogene 2005; 24: 4873–4882.

    CAS  Article  Google Scholar 

  7. 7

    Eilbracht J, Kneissel S, Hofmann A, Schmidt-Zachmann MS . Protein NO52—a constitutive nucleolar component sharing high sequence homologies to protein NO66. Eur J Cell Biol 2005; 84: 279–294.

    CAS  Article  Google Scholar 

  8. 8

    Tan XP, Dong WG, Zhang Q, Yang ZR, Lei XF, Ai MH . Potential effects of Mina53 on tumor growth in human pancreatic cancer. Cell Biochem Biophys 2014; 69: 619–625.

    CAS  Article  Google Scholar 

  9. 9

    Xing J, Wang K, Liu PW, Miao Q, Chen XY . Mina53, a novel molecular marker for the diagnosis and prognosis of gastric adenocarcinoma. Oncol Rep 2014; 31: 634–640.

    CAS  Article  Google Scholar 

  10. 10

    Lu Y, Chang Q, Zhang Y, Beezhold K, Rojanasakul Y, Zhao H et al. Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3. Cell Cycle 2009; 8: 2101–2109.

    CAS  Article  Google Scholar 

  11. 11

    Komiya K, Sueoka-Aragane N, Sato A, Hisatomi T, Sakuragi T, Mitsuoka M et al. Expression of Mina53, a novel c-Myc target gene, is a favorable prognostic marker in early stage lung cancer. Lung Cancer 2010; 69: 232–238.

    Article  Google Scholar 

  12. 12

    Teye K, Arima N, Nakamura Y, Sakamoto K, Sueoka E, Kimura H et al. Expression of Myc target gene mina53 in subtypes of human lymphoma. Oncol Rep 2007; 18: 841–848.

    CAS  PubMed  Google Scholar 

  13. 13

    Teye K, Tsuneoka M, Arima N, Koda Y, Nakamura Y, Ueta Y et al. Increased expression of a Myc target gene Mina53 in human colon cancer. Am J Pathol 2004; 164: 205–216.

    CAS  Article  Google Scholar 

  14. 14

    Tsuneoka M, Fujita H, Arima N, Teye K, Okamura T, Inutsuka H et al. Mina53 as a potential prognostic factor for esophageal squamous cell carcinoma. Clin Cancer Res 2004; 10: 7347–7356.

    CAS  Article  Google Scholar 

  15. 15

    Fukahori S, Yano H, Tsuneoka M, Tanaka Y, Yagi M, Kuwano M et al. Immunohistochemical expressions of Cap43 and Mina53 proteins in neuroblastoma. J Pediatr Surg 2007; 42: 1831–1840.

    Article  Google Scholar 

  16. 16

    Tan XP, Zhang Q, Dong WG, Lei XW, Yang ZR . Upregulated expression of Mina53 in cholangiocarcinoma and its clinical significance. Oncol Lett 2012; 3: 1037–1041.

    Article  Google Scholar 

  17. 17

    Yu M, Sun J, Thakur C, Chen B, Lu Y, Zhao H et al. Paradoxical roles of mineral dust induced gene on cell proliferation and migration/invasion. PLoS One 2014; 9: e87998.

    Article  Google Scholar 

  18. 18

    Lin H, Wang Y, Wang Y, Tian F, Pu P, Yu Y et al. Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans. Cell Res 2010; 20: 899–907.

    CAS  Article  Google Scholar 

  19. 19

    Chowdhury R, Sekirnik R, Brissett NC, Krojer T, Ho CH, Ng SS et al. Ribosomal oxygenases are structurally conserved from prokaryotes to humans. Nature 2014; 510: 422–426.

    CAS  Article  Google Scholar 

  20. 20

    Chen B, Yu M, Chang Q, Lu Y, Thakur C, Ma D et al. Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by down-regulating H3K9me3 and heterochromatin. Oncotarget 2013; 4: 1427–1437.

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Cohen I, Poreba E, Kamieniarz K, Schneider R . Histone modifiers in cancer: friends or foes? Genes Cancer 2011; 2: 631–647.

    CAS  Article  Google Scholar 

  22. 22

    Lim S, Kaldis P . Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013; 140: 3079–3093.

    CAS  Article  Google Scholar 

  23. 23

    Kouzarides T . Chromatin modifications and their function. Cell 2007; 128: 693–705.

    CAS  Article  Google Scholar 

  24. 24

    Jenuwein T, Allis CD . Translating the histone code. Science 2001; 293: 1074–1080.

    CAS  Article  Google Scholar 

  25. 25

    Li B, Carey M, Workman JL . The role of chromatin during transcription. Cell 2007; 128: 707–719.

    CAS  Article  Google Scholar 

  26. 26

    Shilatifard A . Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 2006; 75: 243–269.

    CAS  Article  Google Scholar 

  27. 27

    Kim TD, Shin S, Berry WL, Oh S, Janknecht R . The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells. J Cell Biochem 2012; 113: 1368–1376.

    CAS  Article  Google Scholar 

  28. 28

    Toyokawa G, Cho HS, Iwai Y, Yoshimatsu M, Takawa M, Hayami S et al. The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6. Cancer Prev Res (Phila) 2011; 4: 2051–2061.

    CAS  Article  Google Scholar 

  29. 29

    Zhao E, Ding J, Xia Y, Liu M, Ye B, Choi JH et al. KDM4C and ATF4 cooperate in transcriptional control of amino acid metabolism. Cell Rep 2016; 14: 506–519.

    CAS  Article  Google Scholar 

  30. 30

    Komiya K, Sueoka-Aragane N, Sato A, Hisatomi T, Sakuragi T, Mitsuoka M et al. Mina53, a novel c-Myc target gene, is frequently expressed in lung cancers and exerts oncogenic property in NIH/3T3 cells. J Cancer Res Clin Oncol 2010; 136: 465–473.

    CAS  Article  Google Scholar 

  31. 31

    Wang M, Liu Y, Zou J, Yang R, Xuan F, Wang Y et al. Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β. Oncotarget 2015; 6: 9517–9530.

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Yang R, Wu Y, Wang M, Sun Z, Zou J, Zhang Y et al. HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation. Oncotarget 2015; 6: 7644–7656.

    PubMed  PubMed Central  Google Scholar 

  33. 33

    Xuan F, Huang M, Liu W, Ding H, Yang L, Cui H . Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1. Neuro Oncol 2015; 18: 819–829.

    Article  Google Scholar 

Download references


This work was supported by the National Basic Research Program of China (No. 2012CB114603), the National Natural Science Foundation of China (No. 31501100, 81502574), the Research Fund for the Doctoral Program of Higher Education of China (20130182110003) and the Basal Research Fund of Central Higher Education Institutions (XDJK2016D003).

Author information



Corresponding author

Correspondence to H-J Cui.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huang, MY., Xuan, F., Liu, W. et al. MINA controls proliferation and tumorigenesis of glioblastoma by epigenetically regulating cyclins and CDKs via H3K9me3 demethylation. Oncogene 36, 387–396 (2017). https://doi.org/10.1038/onc.2016.208

Download citation

Further reading


Quick links