Skip to main content
SpringerLink
Log in

Octamer transcription factor-1 induces the Warburg effect via up-regulation of hexokinase 2 in non-small cell lung cancer

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Reprogramming of energy metabolism is a hallmark of cancer which is prevalent worldwide. Octamer transcription factor-1 (OCT1) is a well-known transcription factor. However, the role of OCT1 in metabolism remodeling has not been well defined. In the present study, we found that OCT1 was up-regulated in non-small cell lung cancer (NSCLC) and correlated with poor patient survival. Further data identified that OCT1 increased glycolysis flux, promoting proliferation in lung cancer cells. Mechanistically, OCT1 facilitated the aerobic glycolysis and cell proliferation via up-regulation of hexokinase 2 (HK2), a crucial enzyme of the Warburg effect. Hence, our findings indicate that, in NSCLC, high levels of OCT1 contribute to the Warburg effect through up-regulation of HK2, linking up the OCT1/HK2 axis and cancer progression, which provide a potential biomarker and therapeutic target for NSCLC treatment.

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

Similar content being viewed by others

Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

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 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. Warburg O (1956) On the origin of cancer cells. Science 123:309–314. https://doi.org/10.1126/science.123.3191.309

    Article  CAS  PubMed  Google Scholar 

  3. Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270

    CAS  PubMed  Google Scholar 

  4. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. https://doi.org/10.1126/science.1160809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  6. Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10:671–684. https://doi.org/10.1038/nrd3504

    Article  CAS  PubMed  Google Scholar 

  7. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G (2013) Metabolic targets for cancer therapy. Nat Rev Drug Discov 12:829–846. https://doi.org/10.1038/nrd4145

    Article  CAS  PubMed  Google Scholar 

  8. Yeung SJ, Pan J, Lee MH (2008) Roles of p53, MYC and HIF-1 in regulating glycolysis—the seventh hallmark of cancer. Cell Mol Life Sci 65:3981–3999. https://doi.org/10.1007/s00018-008-8224-x

    Article  CAS  PubMed  Google Scholar 

  9. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20. https://doi.org/10.1016/j.cmet.2007.10.002

    Article  CAS  PubMed  Google Scholar 

  10. Dejure FR, Eilers M (2017) MYC and tumor metabolism: chicken and egg. EMBO J 36:3409–3420. https://doi.org/10.15252/embj.201796438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Herr W, Sturm RA, Clerc RG, Corcoran LM, Baltimore D, Sharp PA, Ingraham HA, Rosenfeld MG, Finney M, Ruvkun G et al (1988) The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev 2:1513–1516. https://doi.org/10.1101/gad.2.12a.1513

    Article  CAS  PubMed  Google Scholar 

  12. Ryan AK, Rosenfeld MG (1997) POU domain family values: flexibility, partnerships, and developmental codes. Genes Dev 11:1207–1225. https://doi.org/10.1101/gad.11.10.1207

    Article  CAS  PubMed  Google Scholar 

  13. Kang J, Gemberling M, Nakamura M, Whitby FG, Handa H, Fairbrother WG, Tantin D (2009) A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress. Genes Dev 23:208–222. https://doi.org/10.1101/gad.1750709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kang J, Shakya A, Tantin D (2009) Stem cells, stress, metabolism and cancer: a drama in two Octs. Trends Biochem Sci 34:491–499. https://doi.org/10.1016/j.tibs.2009.06.003

    Article  CAS  PubMed  Google Scholar 

  15. Maddox J, Shakya A, South S, Shelton D, Andersen JN, Chidester S, Kang J, Gligorich KM, Jones DA, Spangrude GJ, Welm BE, Tantin D (2012) Transcription factor Oct1 is a somatic and cancer stem cell determinant. PLoS Genet 8:e1003048. https://doi.org/10.1371/journal.pgen.1003048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vázquez-Arreguín K, Tantin D (2016) The Oct1 transcription factor and epithelial malignancies: old protein learns new tricks. Biochim Biophys Acta 1859:792–804. https://doi.org/10.1016/j.bbagrm.2016.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Obinata D, Takayama K, Urano T, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K, Homma Y, Ouchi Y, Takahashi S, Inoue S (2012) Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer. Int J Cancer 130:1021–1028. https://doi.org/10.1002/ijc.26043

    Article  CAS  PubMed  Google Scholar 

  18. Jeong SH, Lee YJ, Cho BI, Ha WS, Choi SK, Jung EJ, Ju YT, Jeong CY, Ko GH, Yoo J, Hong SC (2014) OCT-1 overexpression is associated with poor prognosis in patients with well-differentiated gastric cancer. Tumour Biol 35:5501–5509. https://doi.org/10.1007/s13277-014-1724-4

    Article  CAS  PubMed  Google Scholar 

  19. Vázquez-Arreguín K, Maddox J, Kang J, Park D, Cano RR, Factor RE, Ludwig T, Tantin D (2018) BRCA1 through its E3 ligase activity regulates the transcription factor Oct1 and carbohydrate metabolism. Mol Cancer Res 16:439–452. https://doi.org/10.1158/1541-7786.Mcr-17-0364

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vázquez-Arreguín K, Bensard C, Schell JC, Swanson E, Chen X, Rutter J, Tantin D (2019) Oct1/Pou2f1 is selectively required for colon regeneration and regulates colon malignancy. PLoS Genet 15:e1007687. https://doi.org/10.1371/journal.pgen.1007687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shakya A, Cooksey R, Cox JE, Wang V, McClain DA, Tantin D (2009) Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nat Cell Biol 11:320–327. https://doi.org/10.1038/ncb1840

    Article  CAS  PubMed  Google Scholar 

  22. Qi Q, Liu X, Li S, Joshi HC, Ye K (2013) Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth. Acta Pharmacol Sin 34:930–938. https://doi.org/10.1038/aps.2013.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. D’Addario G, Früh M, Reck M, Baumann P, Klepetko W, Felip E (2010) Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v116–v119. https://doi.org/10.1093/annonc/mdq189

    Article  PubMed  Google Scholar 

  24. Tantin D, Schild-Poulter C, Wang V, Haché RJ, Sharp PA (2005) The octamer binding transcription factor Oct-1 is a stress sensor. Cancer Res 65:10750–10758. https://doi.org/10.1158/0008-5472.Can-05-2399

    Article  CAS  PubMed  Google Scholar 

  25. Li L, Liang Y, Kang L, Liu Y, Gao S, Chen S, Li Y, You W, Dong Q, Hong T, Yan Z, Jin S, Wang T, Zhao W, Mai H, Huang J, Han X, Ji Q, Song Q, Yang C, Zhao S, Xu X, Ye Q (2018) Transcriptional regulation of the Warburg effect in cancer by SIX1. Cancer Cell 33:368-385.e7. https://doi.org/10.1016/j.ccell.2018.01.010

    Article  CAS  PubMed  Google Scholar 

  26. Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337. https://doi.org/10.1038/nrc3038

    Article  CAS  PubMed  Google Scholar 

  27. Patra KC, Hay N (2013) Hexokinase 2 as oncotarget. Oncotarget 4:1862–1863. https://doi.org/10.18632/oncotarget.1563

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hay N (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16:635–649. https://doi.org/10.1038/nrc.2016.77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey B, Hay N (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213–228. https://doi.org/10.1016/j.ccr.2013.06.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roberts DJ, Miyamoto S (2015) Hexokinase II integrates energy metabolism and cellular protection: akting on mitochondria and TORCing to autophagy. Cell Death Differ 22:248–257. https://doi.org/10.1038/cdd.2014.173

    Article  CAS  PubMed  Google Scholar 

  31. DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR, Hay N (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446. https://doi.org/10.1038/s41467-017-02733-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Heikkinen S, Pietila M, Halmekyto M, Suppola S, Pirinen E, Deeb SS, Janne J, Laakso M (1999) Hexokinase II-deficient mice. Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes. J Biol Chem 274:22517–22523. https://doi.org/10.1074/jbc.274.32.22517

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Dr. Bin Lv (Wenzhou Medical University) for providing clinical lung samples. This research was funded by National Natural Science Foundation of China (81973341, 81902826), Science and Technology Program of Guangzhou (202002030010), and the Fundamental Research Funds for the Central Universities (21620426).

Author information

Authors and Affiliations

  1. Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, China

    Zhen Li

  2. MOE Key Laboratory of Tumor Molecular Biology, Department of Pharmacology, Clinical Translational Center for Targeted Drug, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China

    Jin Su & Qi Qi

  3. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China

    Mingming Sun, Jiaqi Song, Huanran Sun & Changliang Shan

  4. Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China

    Jun Fan & Guo Chen

  5. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China

    Shuai Zhang

Authors
  1. Zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingming Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiaqi Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huanran Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Changliang Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qi Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shuai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Qi Qi or Shuai Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was carried out in accordance with the recommendations of Requirements of the Ethical Review System of Biomedical Research Involving Human by National Health and Family Planning Commission of China, Jinan University and Wenzhou Medical University Ethics Committee with written informed consent from all subjects.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Su, J., Sun, M. et al. Octamer transcription factor-1 induces the Warburg effect via up-regulation of hexokinase 2 in non-small cell lung cancer. Mol Cell Biochem 476, 3423–3431 (2021). https://doi.org/10.1007/s11010-021-04171-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04171-9

Keywords

Search

Navigation