FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion

Yun Zheng, Jinjun Guo, Jin Zhou, Jinjian Lu, Qi Chen, Cui Zhang, Chen Qing, H. Philip Koeffler, Yunguang Tong

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Abstract Background: Metastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments. Methods: Illumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer. Results: Analyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ∼ 0.89, p = 2.1E-226 ∼ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the -600 to -300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the -391 to -385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR<0.05) differentially expressed between WT and PTTG1<sup>-/-</sup> HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1. Conclusions: PTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.

Original languageEnglish (US)
Article number126
JournalBMC Medical Genomics
Volume8
Issue number1
DOIs
StatePublished - Aug 12 2015

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Cell Movement
Colorectal Neoplasms
Neoplasm Metastasis
HCT116 Cells
Chromatin Immunoprecipitation
Microarray Analysis
Luciferases
Liver
Genes
Neoplasms
Pituitary Neoplasms
Genomics
Computational Biology
Oncogenes
Genetic Promoter Regions
Injections

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion. / Zheng, Yun; Guo, Jinjun; Zhou, Jin; Lu, Jinjian; Chen, Qi; Zhang, Cui; Qing, Chen; Koeffler, H. Philip; Tong, Yunguang.

In: BMC Medical Genomics, Vol. 8, No. 1, 126, 12.08.2015.

Research output: Contribution to journalArticle

Zheng, Y, Guo, J, Zhou, J, Lu, J, Chen, Q, Zhang, C, Qing, C, Koeffler, HP & Tong, Y 2015, 'FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion', BMC Medical Genomics, vol. 8, no. 1, 126. https://doi.org/10.1186/s12920-015-0126-9
Zheng, Yun ; Guo, Jinjun ; Zhou, Jin ; Lu, Jinjian ; Chen, Qi ; Zhang, Cui ; Qing, Chen ; Koeffler, H. Philip ; Tong, Yunguang. / FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion. In: BMC Medical Genomics. 2015 ; Vol. 8, No. 1.
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abstract = "Abstract Background: Metastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments. Methods: Illumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer. Results: Analyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ∼ 0.89, p = 2.1E-226 ∼ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the -600 to -300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the -391 to -385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR<0.05) differentially expressed between WT and PTTG1-/- HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1. Conclusions: PTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.",
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AU - Zheng, Yun

AU - Guo, Jinjun

AU - Zhou, Jin

AU - Lu, Jinjian

AU - Chen, Qi

AU - Zhang, Cui

AU - Qing, Chen

AU - Koeffler, H. Philip

AU - Tong, Yunguang

PY - 2015/8/12

Y1 - 2015/8/12

N2 - Abstract Background: Metastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments. Methods: Illumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer. Results: Analyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ∼ 0.89, p = 2.1E-226 ∼ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the -600 to -300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the -391 to -385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR<0.05) differentially expressed between WT and PTTG1-/- HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1. Conclusions: PTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.

AB - Abstract Background: Metastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments. Methods: Illumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer. Results: Analyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ∼ 0.89, p = 2.1E-226 ∼ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the -600 to -300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the -391 to -385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR<0.05) differentially expressed between WT and PTTG1-/- HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1. Conclusions: PTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.

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