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Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant

  • Liming HuangEmail author
  • Wenshen Xu
  • Danfang Yan
  • Xin You
  • Xi Shi
  • Shu Zhang
  • Hualan Hong
  • Lian DaiEmail author
Original Research
  • 27 Downloads

Abstract

Mitogen-activated protein kinase-associated protein 1 (MAPKAP1) is a unique component of the mechanistic target of rapamycin (MTOR) pathway which plays a pivotal role in carcinogenesis. The role of enhancer variant in carcinogenesis receives increased attentions. However, the significance of enhancer variants of MAPKAP1 in glioma has not yet been investigated. The associations of enhancer variants of MAPKAP1 with glioma susceptibility were evaluated in a cohort of 400 glioma patients and 651 controls. The function of glioma susceptibility locus was examined by a set of biochemical assays. We found that an enhancer variant of MAPKAP1 rs473426 was associated with a significantly increased risk of glioma in a dominant manner (OR 1.53, 95% CI 1.13–2.06; P = 0.006). The association for rs1339499 located in the same enhancer approached the borderline of significance after multiple testing correction (OR 0.74, 95% CI 0.56–0.98; P = 0.037). Furthermore, cumulative associations of rs473426 and rs1339499 with glioma risk were observed (P = 0.011). Functional analyses showed that the risk allele rs473426 C downregulated the regulatory activity of enhancer by reducing the binding affinity of a transcriptional activator NFΙC, which resulted in lower gene expression both in vitro and in vivo. These results demonstrate for the first time that enhancer variant of MAPKAP1 confers susceptibility to glioma by downregulation of MAPKAP1 expression, and provide further evidence highlighting MAPKAP1 as a cancer suppressor in glioma carcinogenesis.

Keywords

Glioma MAPKAP1 Enhancer Genetic variation Susceptibility 

Abbreviations

MAPKAP1

Mitogen-activated protein kinase-associated protein 1

MTOR

Mechanistic target of rapamycin

GWAS

Genome-wide association study

MTORC2

MTOR complex 2

CHS

Southern Han Chinese

MAF

Minor allelic frequency

LD

Linkage disequilibrium

EMSA

Electrophoretic mobility-shift assay

ChIP

Chromatin immunoprecipitation assay

OR

Odds ratio

CI

Confidence interval

Notes

Author Contributions

LMH, WSX, DFY, XY, XS, SZ, HLH and LD participated in the study design. LMH, WSX, DFY, XY, SZ, HLH and LD performed the experiment. LMH, WSX, DFY, XY, XS, SZ and LD were involved in data collection and data interpretation. LMH, WSX, DFY, XY and LD participated in the statistical analyses. LMH and LD wrote the manuscript. All authors read and approved the final manuscript.

Funding

This work was funded by National Natural Science Foundation, P.R.C (Grant Number 81301772); Joint Funds for the Innovation of Science and Technology of Fujian province, P.R.C (Grant Number 2016Y9016); Natural Science Foundation of Fujian Province, P.R.C (Grant Number 2014J05087); and Startup Fund for Scientific Research of Fujian Medical University (Grant Number 2017XQ1085).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10571_2019_763_MOESM1_ESM.pdf (239 kb)
Supplementary material 1 (PDF 239 kb)

References

  1. 1000 Genomes Project Consortium et al (2015) A global reference for human genetic variation. Nature 526:68CrossRefGoogle Scholar
  2. Adel Fahmideh M, Schwartzbaum J, Frumento P, Feychting M (2014) Association between DNA repair gene polymorphisms and risk of glioma: a systematic review and meta-analysis. Neuro Oncol 16:807–814CrossRefGoogle Scholar
  3. Auton A et al (2015) A global reference for human genetic variation. Nature 526:68–74CrossRefGoogle Scholar
  4. Barrett JC (2009) Haploview: visualization and analysis of SNP genotype data. Cold Spring Harb Protoc.  https://doi.org/10.1101/pdb.ip71 CrossRefPubMedGoogle Scholar
  5. Barrett T et al (2013) NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res 41:D991–995CrossRefGoogle Scholar
  6. Cameron AJ, Linch MD, Saurin AT, Escribano C, Parker PJ (2011) mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem J 439:287–297CrossRefGoogle Scholar
  7. Cheng J, Zhang D, Kim K, Zhao Y, Zhao Y, Su B (2005) Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation. Mol Cell Biol 25:5955–5964CrossRefGoogle Scholar
  8. Flicek P et al (2014) Ensembl 2014. Nucleic Acids Res 42:D749–755CrossRefGoogle Scholar
  9. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16:1865–1870CrossRefGoogle Scholar
  10. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22CrossRefGoogle Scholar
  11. Guertin DA et al (2009) mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15:148–159CrossRefGoogle Scholar
  12. Hernandez DG et al (2012) Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain. Neurobiol Dis 47:20–28CrossRefGoogle Scholar
  13. Herz HM (2016) Enhancer deregulation in cancer and other diseases. BioEssays 38:1003–1015CrossRefGoogle Scholar
  14. Hietakangas V, Cohen SM (2008) TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells. BMC Cancer 8:282CrossRefGoogle Scholar
  15. Hu Z, Wang Y, Wang Y, Zang B, Hui H, You Z, Wang X (2017) Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition. Biochem Biophys Res Commun 483:645–651CrossRefGoogle Scholar
  16. Huang L, Xu W, Yan D, Dai L, Shi X (2016) Identification of expression quantitative trait loci of RPTOR for susceptibility to glioma. Tumour Biol 37:2305–2311CrossRefGoogle Scholar
  17. Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37:19–24CrossRefGoogle Scholar
  18. International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796CrossRefGoogle Scholar
  19. Jacinto E et al (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137CrossRefGoogle Scholar
  20. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293CrossRefGoogle Scholar
  21. Lapointe S, Perry A, Butowski NA (2018) Primary brain tumours in adults. Lancet 392:432–446CrossRefGoogle Scholar
  22. Liu P et al (2015) PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov 5:1194–1209CrossRefGoogle Scholar
  23. Louis DN et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefGoogle Scholar
  24. Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J (2007) mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 67:11712–11720CrossRefGoogle Scholar
  25. Masui K et al (2013) mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab 18:726–739CrossRefGoogle Scholar
  26. McNamara S (2012) Treatment of primary brain tumours in adults. Nurs Stand 27:42–47CrossRefGoogle Scholar
  27. Ostrom QT, Gittleman H, Stetson L, Virk S, Barnholtz-Sloan JS (2018) Epidemiology of intracranial gliomas. Prog Neurol Surg 30:1–11CrossRefGoogle Scholar
  28. Paten B, Herrero J, Beal K, Fitzgerald S, Birney E (2008) Enredo and Pecan: genome-wide mammalian consistency-based multiple alignment with paralogs. Genome Res 18:1814–1828CrossRefGoogle Scholar
  29. Schroder WA, Buck M, Cloonan N, Hancock JF, Suhrbier A, Sculley T, Bushell G (2007) Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cell Signal 19:1279–1289CrossRefGoogle Scholar
  30. Tatebe H et al (2017) Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit. eLife 6:10CrossRefGoogle Scholar
  31. Visel A, Minovitsky S, Dubchak I, Pennacchio LA (2007) VISTA Enhancer Browser–a database of tissue-specific human enhancers. Nucleic Acids Res 35:D88–92CrossRefGoogle Scholar
  32. Wang D, Wu P, Wang H, Zhu L, Zhao W, Lu Y (2016) SIN1 promotes the proliferation and migration of breast cancer cells by Akt activation. Biosci Rep 36:e00424CrossRefGoogle Scholar
  33. Wenzelides S, Altmann H, Wendler W, Winnacker EL (1996) CTF5–a new transcriptional activator of the NFI/CTF family. Nucleic Acids Res 24:2416–2421CrossRefGoogle Scholar
  34. Xiao Q et al (2014) 9q33.3, a stress-related chromosome region, contributes to reducing lung squamous cell carcinoma risk. J Thorac Oncol 9:1041–1047CrossRefGoogle Scholar
  35. Xu J, Li X, Yang H, Chang R, Kong C, Yang L (2013) SIN1 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial-mesenchymal transition. Cancer 119:2247–2257CrossRefGoogle Scholar
  36. Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20:2820–2832CrossRefGoogle Scholar
  37. Yang HC, Lin CW, Chen CW, Chen JJ (2014) Applying genome-wide gene-based expression quantitative trait locus mapping to study population ancestry and pharmacogenetics. BMC Genomics 15:319CrossRefGoogle Scholar
  38. Yang G, Murashige DS, Humphrey SJ, James DE (2015) A positive feedback loop between Akt and mTORC2 via SIN1 phosphorylation. Cell Rep 12:937–943CrossRefGoogle Scholar
  39. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical Oncology (39th Section)The First Affiliated Hospital, Fujian Medical UniversityFuzhouChina
  2. 2.Department of Laboratory MedicineThe First Affiliated Hospital, Fujian Medical UniversityFuzhouChina
  3. 3.Department of Radiation OncologyThe First Affiliated Hospital, Zhejiang UniversityHangzhouChina
  4. 4.Department of MedicineThe Third Affiliated People’s Hospital, Fujian University of Traditional Chinese MedicineFuzhouChina

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