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:

The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect

Oncogene volume 38, pages 483–496 (2019)Cite this article

Subjects

Abstract

Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.

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
Fig. 7

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2015;65:5–29.

    Article  Google Scholar 

  2. Wu WK, Law PT, Lee CW, Cho CH, Fan D, Wu K, et al. MicroRNA in colorectal cancer: from benchtop to bedside. Carcinogenesis. 2011;32:247–53.

    Article  CAS  Google Scholar 

  3. Cekaite L, Eide PW, Lind GE, Skotheim RI, Lothe RA. MicroRNAs as growth regulators, their function and biomarker status in colorectal cancer. Oncotarget. 2016;7:6476–505.

    Article  Google Scholar 

  4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  5. Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017;14:11–31.

    Article  CAS  Google Scholar 

  6. Weber GF. Time and circumstances: cancer cell metabolism at various stages of disease progression. Front Oncol. 2016;6:257.

    Article  Google Scholar 

  7. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

    Article  CAS  Google Scholar 

  8. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Article  Google Scholar 

  9. Wechalekar K, Sharma B, Cook G. PET/CT in oncology—a major advance. Clin Radiol. 2005;60:1143–55.

    Article  CAS  Google Scholar 

  10. Velpula KK, Bhasin A, Asuthkar S, Tsung AJ. Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect. Cancer Res. 2013;73:7277–89.

    Article  CAS  Google Scholar 

  11. Zhang Y, Yang JM. Altered energy metabolism in cancer: a unique opportunity for therapeutic intervention. Cancer Biol Ther. 2013;14:81–9.

    Article  CAS  Google Scholar 

  12. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14:1295–304.

    Article  CAS  Google Scholar 

  13. Marin-Hernandez A, Rodriguez-Enriquez S, Vital-Gonzalez PA, Flores-Rodriguez FL, Macias-Silva M, Sosa-Garrocho M, et al. Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase. FEBS J. 2006;273:1975–88.

    Article  CAS  Google Scholar 

  14. Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD, Mathew LK, et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature. 2014;513:251–5.

    Article  CAS  Google Scholar 

  15. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013;23:316–31.

    Article  CAS  Google Scholar 

  16. Liu X, Wang X, Zhang J, Lam EK, Shin VY, Cheng AS, et al. Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis. Oncogene. 2010;29:442–50.

    Article  CAS  Google Scholar 

  17. Zhang J, Wang J, Xing H, Li Q, Zhao Q, Li J. Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells. Mol Cell Biochem. 2016;411:331–40.

    Article  CAS  Google Scholar 

  18. Zhu Y, Shi M, Chen H, Gu J, Zhang J, Shen B, et al. NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells. Oncotarget. 2015;6:21443–51.

    PubMed  PubMed Central  Google Scholar 

  19. Hirata H, Sugimachi K, Komatsu H, Ueda M, Masuda T, Uchi R, et al. Decreased expression of fructose-1,6-bisphosphatase associates with glucose metabolism and tumor progression in hepatocellular carcinoma. Cancer Res. 2016;76:3265–76.

    Article  CAS  Google Scholar 

  20. Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development. 2016;143:4558–70.

    Article  CAS  Google Scholar 

  21. Hannenhalli S, Kaestner KH. The evolution of Fox genes and their role in development and disease. Nat Rev Genet. 2009;10:233–40.

    Article  CAS  Google Scholar 

  22. Li Q, Wu J, Wei P, Xu Y, Zhuo C, Wang Y, et al. Overexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial–mesenchymal transition. Am J Cancer Res. 2015;5:2022–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Weng W, Okugawa Y, Toden S, Toiyama Y, Kusunoki M, Goel A. FOXM1 and FOXQ1 are promising prognostic biomarkers and novel targets of tumor suppressive miR-342 in human colorectal cancer. Clin Cancer Res. 2016;22:4947–57.

    Article  CAS  Google Scholar 

  24. Sun J, Li H, Huo Q, Cui M, Ge C, Zhao F, et al. The transcription factor FOXN3 inhibits cell proliferation by downregulating E2F5 expression in hepatocellular carcinoma cells. Oncotarget. 2016;7:43534–45.

    PubMed  PubMed Central  Google Scholar 

  25. Cui J, Shi M, Xie D, Wei D, Jia Z, Zheng S, et al. FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clin Cancer Res. 2014;20:2595–606.

    Article  CAS  Google Scholar 

  26. Xia L, Huang W, Tian D, Zhu H, Qi X, Chen Z, et al. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology. 2013;57:610–24.

    Article  CAS  Google Scholar 

  27. Paylakhi SH, Moazzeni H, Yazdani S, Rassouli P, Arefian E, Jaberi E, et al. FOXC1 in human trabecular meshwork cells is involved in regulatory pathway that includes miR-204, MEIS2, and ITGbeta1. Exp Eye Res. 2013;111:112–21.

    Article  CAS  Google Scholar 

  28. Khan AO, Aldahmesh MA, Mohamed JY, Alkuraya FS. Congenital glaucoma with acquired peripheral circumferential iris degeneration. J AAPOS. 2013;17:105–7.

    Article  Google Scholar 

  29. Ray PS, Wang J, Qu Y, Sim MS, Shamonki J, Bagaria SP, et al. FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res. 2010;70:3870–6.

    Article  CAS  Google Scholar 

  30. Xu ZY, Ding SM, Zhou L, Xie HY, Chen KJ, Zhang W, et al. FOXC1 contributes to microvascular invasion in primary hepatocellular carcinoma via regulating epithelial–mesenchymal transition. Int J Biol Sci. 2012;8:1130–41.

    Article  CAS  Google Scholar 

  31. Wang L, Gu F, Liu CY, Wang RJ, Li J, Xu JY. High level of FOXC1 expression is associated with poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. 2013;34:853–8.

    Article  CAS  Google Scholar 

  32. Nagel S, Meyer C, Kaufmann M, Drexler HG, MacLeod RA. Deregulated FOX genes in Hodgkin lymphoma. Genes Chromosomes Cancer. 2014;53:917–33.

    Article  CAS  Google Scholar 

  33. Wei LX, Zhou RS, Xu HF, Wang JY, Yuan MH. High expression of FOXC1 is associated with poor clinical outcome in non-small cell lung cancer patients. Tumour Biol. 2013;34:941–6.

    Article  CAS  Google Scholar 

  34. Somerville TD, Wiseman DH, Spencer GJ, Huang X, Lynch JT, Leong HS, et al. Frequent derepression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukemia. Cancer Cell. 2015;28:329–42.

    Article  CAS  Google Scholar 

  35. Huang W, Chen Z, Zhang L, Tian D, Wang D, Fan D, et al. Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice. Gastroenterology. 2015;149:1053–67 e14.

    Article  CAS  Google Scholar 

  36. Aravalli RN, Greten TF. FoxC1: Novel regulator of inflammation-induced metastasis in hepatocellular carcinoma. Gastroenterology. 2015;149:861–3.

    Article  Google Scholar 

  37. Jensen TW, Ray T, Wang J, Li X, Naritoku WY, Han B, et al. Diagnosis of basal-like breast cancer using a FOXC1-based assay. J Natl Cancer Inst. 2015;107.

  38. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–21.

    CAS  PubMed  Google Scholar 

  39. Pierrou S, Hellqvist M, Samuelsson L, Enerback S, Carlsson P. Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. EMBO J. 1994;13:5002–12.

    Article  CAS  Google Scholar 

  40. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59.

    Article  CAS  Google Scholar 

  41. Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes beta-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20:427–42.

    Article  CAS  Google Scholar 

  42. Li D, Wei P, Peng Z, Huang C, Tang H, Jia Z, et al. The critical role of dysregulated FOXM1-PLAUR signaling in human colon cancer progression and metastasis. Clin Cancer Res. 2013;19:62–72.

    Article  Google Scholar 

  43. Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol. 2012;30:2956–62.

    Article  CAS  Google Scholar 

  44. Kaneda H, Arao T, Tanaka K, Tamura D, Aomatsu K, Kudo K, et al. FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res. 2010;70:2053–63.

    Article  CAS  Google Scholar 

  45. Wang J, Ray PS, Sim MS, Zhou XZ, Lu KP, Lee AV, et al. FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-kappaB signaling. Oncogene. 2012;31:4798–802.

    Article  CAS  Google Scholar 

  46. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008;8:705–13.

    Article  CAS  Google Scholar 

  47. Kondaveeti Y, Guttilla Reed IK, White BA. Epithelial–mesenchymal transition induces similar metabolic alterations in two independent breast cancer cell lines. Cancer Lett. 2015;364:44–58.

    Article  CAS  Google Scholar 

  48. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep. 2015;42:841–51.

    Article  CAS  Google Scholar 

  49. Dang CV The interplay between MYC and HIF in the Warburg effect. Ernst Schering Foundation Symp. Proc; 2007. p. 35–53.

  50. Li D, Peng Z, Tang H, Wei P, Kong X, Yan D, et al. KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis. Clin Cancer Res. 2011;17:3558–68.

    Article  CAS  Google Scholar 

  51. Li Q, Wei P, Huang B, Xu Y, Li X, Li Y, et al. MAEL expression links epithelial–mesenchymal transition and stem cell properties in colorectal cancer. Int J Cancer. 2016;139:2502–11.

    Article  CAS  Google Scholar 

  52. Zhou A, Lin K, Zhang S, Chen Y, Zhang N, Xue J, et al. Nuclear GSK3beta promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nat Cell Biol. 2016;18:954–66.

    Article  CAS  Google Scholar 

  53. Quan M, Cui J, Xia T, Jia Z, Xie D, Wei D, et al. Merlin/NF2 suppresses pancreatic tumor growth and metastasis by attenuating the FOXM1-mediated Wnt/beta-catenin signaling. Cancer Res. 2015;75:4778–89.

    Article  CAS  Google Scholar 

  54. Guo K, Cui J, Quan M, Xie D, Jia Z, Wei D, et al. The Novel KLF4/MSI2 signaling pathway regulates growth and metastasis of pancreatic cancer. Clin Cancer Res. 2017;23:687–96.

    Article  CAS  Google Scholar 

  55. Li Q, Qin Y, Wei P, Lian P, Li Y, Xu Y, et al. Gas1 inhibits metastatic and metabolic phenotypes in colorectal carcinoma. Mol Cancer Res. 2016;14:830–40.

    Article  CAS  Google Scholar 

  56. Shi M, Cui J, Du J, Wei D, Jia Z, Zhang J, et al. A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. Clin Cancer Res. 2014;20:4370–80.

    Article  CAS  Google Scholar 

  57. Li Q, Qin Y, Wei P, Lian P, Li Y, Xu Y, et al. Gas1 inhibits metastatic and metabolic phenotypes in colorectal carcinoma. Mol Cancer Res. 2016;14:830–40.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Don Norwood in the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editorial assistance and Jianping Zhang at the Center for Biomedical Imaging, Fudan University, for assistance in the mouse PET/CT study.

Author contributions

Conception and design: D. Li, K. Xie. Development of methodology: Q. Li, Y. Li, D. Xie. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Q. Li,M. Zhang, S. Cai, D. Li, G. Li, P. Wei, Y. Li, Y. Xu, X. Li, D. Xie. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J Wu, P. Wei, Y. Li, D. Xie. Writing, review, and/or revision of the manuscript: Q. Li, J Wu, D. Li, K. Xie. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Q. Li, Y. Xu, X. Li, K. Xie. Study supervision: D. Li, P. Wei. Other (financial support): S. Cai, D. Li, K. Xie

Funding

This research was supported by grants from the National Science Foundation of China (81472222, 81702353, 81772583, 81572254, 81372646, 81302097, and 81672374) and Shanghai Rising-Star Program(17QA1400900), Shanghai Municipal Natural Science Foundation (17ZR1406400), Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ046), National Key Basic Research Program of China (2014CBA02002) and grants R01-CA129956, R01-CA148954, R01CA152309, R01CA172233, and R01CA195651 from the National Cancer Institute, National Institutes of Health.

Author information

Author notes

  1. These authors contributed equally: Qingguo Li, Ping Wei, Jitao Wu

Authors and Affiliations

  1. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    Qingguo Li, Yaqi Li, Ye Xu, Xinxiang Li, Sanjun Cai & Dawei Li

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

    Qingguo Li, Ping Wei, Meng Zhang, Guichao Li, Yaqi Li, Ye Xu, Xinxiang Li, Sanjun Cai & Dawei Li

  3. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    Ping Wei & Meng Zhang

  4. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    Ping Wei

  5. Department of Urology, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China

    Jitao Wu

  6. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    Guichao Li

  7. Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Dacheng Xie & Keping Xie

Authors
  1. Qingguo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jitao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guichao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yaqi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ye Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xinxiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dacheng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sanjun Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Keping Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dawei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Keping Xie or Dawei Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Q., Wei, P., Wu, J. et al. The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect. Oncogene 38, 483–496 (2019). https://doi.org/10.1038/s41388-018-0469-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0469-8

This article is cited by

Search

Advanced search

Quick links