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.

GTSE1 promotes prostate cancer cell proliferation via the SP1/FOXM1 signaling pathway

Abstract

G2 and S phase-expressed-1 (GTSE1) has been implicated in the pathogenesis of several malignant tumors. However, its specific role in prostate cancer (PCa) remains unclear. In this study, RNA-Seq data from patients with PCa and controls were downloaded from the FIREBROWSE database, and it was found that the GTSE1 mRNA level was significantly upregulated in PCa. Moreover, patients with higher GTSE1 mRNA levels had higher Gleason scores (P < 0.001), a more advanced pT stage (P = 0.011), and a more advanced pN stage (P = 0.006) as well as a shorter time to biochemical recurrence (P = 0.005). In addition, overexpression of GTSE1 could promote proliferation in LNCaP cells, whereas silencing GTSE1 could inhibit the growth of C4-2 cells in vitro and in vivo. Mechanistically, GTSE1 enhanced the expression of FOXM1 by upregulating the SP1 protein level, a transcription factor of FOXM1, which ultimately promoted PCa cell proliferation. In summary, GTSE1 is a new candidate oncogene in the development and progression of PCa, and it can promote PCa cell proliferation via the SP1/FOXM1 signaling pathway.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: GTSE1 expression was upregulated in prostate cancer.
Fig. 2: The mRNA level of GTSE1 correlates with biochemical recurrence in prostate cancer.
Fig. 3: GTSE1 promotes prostate cancer cell proliferation in vitro and in vivo.
Fig. 4: Gene co-expression and enrichment analyses.
Fig. 5: GTSE1 promotes prostate cancer proliferation via the SP1/FOXM1 signaling pathway.
Fig. 6: GTSE1 promotes the proliferation of prostate cancer cell via SP1/FOXM1 signaling pathway.

References

  1. 1.

    Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61:1079–92.

    Article  Google Scholar 

  2. 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  Google Scholar 

  3. 3.

    Barry MJ, Simmons LH. Prevention of prostate cancer morbidity and mortality: primary prevention and early detection. Med Clin N Am. 2017;101:787–806.

    Article  Google Scholar 

  4. 4.

    Wallis CJD, Glaser A, Hu JC, Huland H, Lawrentschuk N, Moon D, et al. Survival and complications following surgery and radiation for localized prostate cancer: an international collaborative review. Eur Urol. 2018;73:11–20.

    Article  Google Scholar 

  5. 5.

    Liu XS, Li H, Song B, Liu X. Polo-like kinase 1 phosphorylation of G2 and S-phase-expressed 1 protein is essential for p53 inactivation during G2 checkpoint recovery. EMBO Rep. 2010;11:626–32.

    CAS  Article  Google Scholar 

  6. 6.

    Monte M, Benetti R, Buscemi G, Sandy P, Del Sal G, Schneider C. The cell cycle-regulated protein human GTSE-1 controls DNA damage-induced apoptosis by affecting p53 function. J Biol Chem. 2003;278:30356–64.

    CAS  Article  Google Scholar 

  7. 7.

    Lee H, Palm J, Grimes SM, Ji HP. The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations. Genome Med. 2015;7:112.

    Article  Google Scholar 

  8. 8.

    Spanswick VJ, Lowe HL, Newton C, Bingham JP, Bagnobianchi A, Kiakos K, et al. Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples. BMC Cancer. 2012;12:436.

    CAS  Article  Google Scholar 

  9. 9.

    D’Errico M, de Rinaldis E, Blasi MF, Viti V, Falchetti M, Calcagnile A, et al. Genome-wide expression profile of sporadic gastric cancers with microsatellite instability. Eur J Cancer. 2009;45:461–9.

    Article  Google Scholar 

  10. 10.

    Wu X, Wang H, Lian Y, Chen L, Gu L, Wang J, et al. GTSE1 promotes cell migration and invasion by regulating EMT in hepatocellular carcinoma and is associated with poor prognosis. Sci Rep. 2017;7:5129.

    Article  Google Scholar 

  11. 11.

    Lin F, Xie YJ, Zhang XK, Huang TJ, Xu HF, Mei Y, et al. GTSE1 is involved in breast cancer progression in p53 mutation-dependent manner. J Exp Clin Cancer Res. 2019;38:152.

    Article  Google Scholar 

  12. 12.

    Guo L, Zhang S, Zhang B, Chen W, Li X, Zhang W, et al. Silencing GTSE-1 expression inhibits proliferation and invasion of hepatocellular carcinoma cells. Cell Biol Toxicol. 2016;32:263–74.

    CAS  Article  Google Scholar 

  13. 13.

    Shi F, Li T, Liu Z, Chen W, Li X, Zhang W, et al. FOXO1: another avenue for treating digestive malignancy? Semin Cancer Biol. 2018;50:124–31.

    CAS  Article  Google Scholar 

  14. 14.

    Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17:104.

    Article  Google Scholar 

  15. 15.

    Jiang S, Yang Z, Di S, Hu W, Ma Z, Chen F, et al. Novel role of forkhead box O 4 transcription factor in cancer: bringing out the good or the bad. Semin Cancer Biol. 2018;50:1–12.

    Article  Google Scholar 

  16. 16.

    Chen Z, Li L, Xu S, Liu Z, Zhou C, Li Z, et al. A Cdh1-FoxM1-Apc axis controls muscle development and regeneration. Cell Death Dis. 2020;11:180.

    Article  Google Scholar 

  17. 17.

    Li Y, Ligr M, McCarron JP, Daniels G, Zhang D, Zhao X, et al. Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion. Clin Cancer Res. 2011;17:4414–24.

    CAS  Article  Google Scholar 

  18. 18.

    Dai Z, Zhu MM, Peng Y, Jin H, Machireddy N, Qian Z, et al. Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodeling and pulmonary hypertension. Am J Respir Crit Care Med. 2018;198:788–802.

    CAS  Article  Google Scholar 

  19. 19.

    Xia L, Mo P, Huang W, Zhang L, Wang Y, Zhu H, et al. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis. 2012;33:2250–9.

    CAS  Article  Google Scholar 

  20. 20.

    Kong X, Li L, Li Z, Le X, Huang C, Jia Z, et al. Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. Cancer Res. 2013;73:3987–96.

    CAS  Article  Google Scholar 

  21. 21.

    Chen PM, Wu TC, Shieh SH, Wu YH, Li MC, Sheu GT, et al. MnSOD promotes tumor invasion via upregulation of FoxM1-MMP2 axis and related with poor survival and relapse in lung adenocarcinomas. Mol Cancer Res. 2013;11:261–71.

    CAS  Article  Google Scholar 

  22. 22.

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

    CAS  Article  Google Scholar 

  23. 23.

    Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, et al. The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res. 2006;66:2153–61.

    CAS  Article  Google Scholar 

  24. 24.

    Puig-Butille JA, Vinyals A, Ferreres JR, Aguilera P, Cabré E, Tell-Martí G, et al. AURKA overexpression is driven by FOXM1 and MAPK/ERK activation in melanoma cells harboring BRAF or NRAS mutations: impact on melanoma prognosis and therapy. J Investig Dermatol. 2017;137:1297–310.

    CAS  Article  Google Scholar 

  25. 25.

    Kongsema M, Wongkhieo S, Khongkow M, Lam EW, Boonnoy P, Vongsangnak W, et al. Molecular mechanism of Forkhead box M1 inhibition by thiostrepton in breast cancer cells. Oncol Rep. 2019;42:953–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Norbury CJ, Zhivotovsky B. DNA damage-induced apoptosis. Oncogene. 2004;23:2797–808.

    CAS  Article  Google Scholar 

  27. 27.

    Ketola K, Munuganti RSN, Davies A, Nip KM, Bishop JL, Zoubeidi A. Targeting prostate cancer subtype 1 by Forkhead Box M1 pathway inhibition. Clin Cancer Res. 2017;23:923–6933.

    Article  Google Scholar 

  28. 28.

    Cao X, Liu L, Yuan Q, Li X, Cui Y, Ren K, et al. Isovitexin reduces carcinogenicity and stemness in hepatic carcinoma stem-like cells by modulating MnSOD and FoxM1. J Exp Clin Cancer Res. 2019;38:264.

    Article  Google Scholar 

  29. 29.

    Yang L, Jin M, Park SJ, Seo SY, Jeong KW. SETD1A promotes proliferation of castration-resistant Prostate cancer cells via FOXM1 transcription. Cancers. 2020;12:1736.

    CAS  Article  Google Scholar 

  30. 30.

    Bai C, Liu X, Qiu C, Zheng J. FoxM1 is regulated by both HIF-1α and HIF-2α and contributes to gastrointestinal stromal tumor progression. Gastric Cancer. 2019;22:91–103.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Natural Science Foundation of China (81874095 and 82072820) and the Guangdong Basic and Applied Basic Research Project Major Program of China (2019B1515120007).

Author information

Affiliations

Authors

Contributions

XW designed the study. WL and WZ conducted experiments and participated in writing the manuscript. XL and YH were responsible for the statistical analysis. YW, QL, and ML collected the clinical specimens and clinical data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xingqiao Wen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China ensured that all sample information was kept confidential.

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

Verify currency and authenticity via CrossMark

Cite this article

Lai, W., Zhu, W., Li, X. et al. GTSE1 promotes prostate cancer cell proliferation via the SP1/FOXM1 signaling pathway. Lab Invest (2020). https://doi.org/10.1038/s41374-020-00510-4

Download citation

Search

Quick links