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.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
Barry MJ, Simmons LH. Prevention of prostate cancer morbidity and mortality: primary prevention and early detection. Med Clin N Am. 2017;101:787–806.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development. 2016;143:4558–70.
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.
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.
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.
Norbury CJ, Zhivotovsky B. DNA damage-induced apoptosis. Oncogene. 2004;23:2797–808.
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.
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.
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.
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.
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).
Conflict of interest
The authors declare that they have no conflict of interest.
The Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China ensured that all sample information was kept confidential.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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