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BRD4 inhibitor inhibits colorectal cancer growth and metastasis.

Hu Y, Zhou J, Ye F, Xiong H, Peng L, Zheng Z, Xu F, Cui M, Wei C, Wang X, Wang Z, Zhu H, Lee P, Zhou M, Jiang B, Zhang DY - Int J Mol Sci (2015)

Bottom Line: We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT).This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro.Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Road, Guangzhou 510515, China. drhuyuan@gmail.com.

ABSTRACT
Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

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Related in: MedlinePlus

BRD4 inhibition impacts transcriptional programs that control cell proliferation and EMT. (A) Apoptosis of HT29 and SW620 cell lines treated with vehicle (DMSO), MS417 (1 µM) or MS417 (12 µM); (B) Protein levels of candidate apoptosis-related factors following vehicle/MS417 treatment (1 and 12 µM) for 48 h; (C) Protein levels of E-cadherin and Vimentin in HT29 or SW620 cell lines treated with vehicle or MS417 (1 and 12 µM). The expression level of each protein was normalized against GAPDH. *p < 0.01; **p < 0.001; n.s. not significant.
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ijms-16-01928-f003: BRD4 inhibition impacts transcriptional programs that control cell proliferation and EMT. (A) Apoptosis of HT29 and SW620 cell lines treated with vehicle (DMSO), MS417 (1 µM) or MS417 (12 µM); (B) Protein levels of candidate apoptosis-related factors following vehicle/MS417 treatment (1 and 12 µM) for 48 h; (C) Protein levels of E-cadherin and Vimentin in HT29 or SW620 cell lines treated with vehicle or MS417 (1 and 12 µM). The expression level of each protein was normalized against GAPDH. *p < 0.01; **p < 0.001; n.s. not significant.

Mentions: Having seen that BRD4 inhibition leads to the reduction of the proliferative ability of CRC cell lines HT29 and SW620, we next tried to elucidate the means by which that effect was generated. We first investigated whether or not the cells were experiencing increased apoptosis as a result of MS417 application. Flow cytometry staining with standard apoptosis markers Annexin V and PI showed minimal increases in the number of apoptotic cells (Figure 3A). Mixed results were observed through Western blotting, with Fas, an important cell surface receptor protein of the TNF receptor family, which induces apoptosis on binding Fas ligand, increased after BRD4 inhibition in both cells (Figure 3B). Interestingly, increased expression of some anti-apoptotic factors (such as XIAP) was also observed in HT29. However, the expression of XIAP decreased in SW620 (Figure 3B). It seems clear that apoptosis was not the controlling factor for BRD4-inhibition mediated suppression of the cells. This result is not surprising, given that cancer cells are generally not believed to be cleared via apoptosis.


BRD4 inhibitor inhibits colorectal cancer growth and metastasis.

Hu Y, Zhou J, Ye F, Xiong H, Peng L, Zheng Z, Xu F, Cui M, Wei C, Wang X, Wang Z, Zhu H, Lee P, Zhou M, Jiang B, Zhang DY - Int J Mol Sci (2015)

BRD4 inhibition impacts transcriptional programs that control cell proliferation and EMT. (A) Apoptosis of HT29 and SW620 cell lines treated with vehicle (DMSO), MS417 (1 µM) or MS417 (12 µM); (B) Protein levels of candidate apoptosis-related factors following vehicle/MS417 treatment (1 and 12 µM) for 48 h; (C) Protein levels of E-cadherin and Vimentin in HT29 or SW620 cell lines treated with vehicle or MS417 (1 and 12 µM). The expression level of each protein was normalized against GAPDH. *p < 0.01; **p < 0.001; n.s. not significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307342&req=5

ijms-16-01928-f003: BRD4 inhibition impacts transcriptional programs that control cell proliferation and EMT. (A) Apoptosis of HT29 and SW620 cell lines treated with vehicle (DMSO), MS417 (1 µM) or MS417 (12 µM); (B) Protein levels of candidate apoptosis-related factors following vehicle/MS417 treatment (1 and 12 µM) for 48 h; (C) Protein levels of E-cadherin and Vimentin in HT29 or SW620 cell lines treated with vehicle or MS417 (1 and 12 µM). The expression level of each protein was normalized against GAPDH. *p < 0.01; **p < 0.001; n.s. not significant.
Mentions: Having seen that BRD4 inhibition leads to the reduction of the proliferative ability of CRC cell lines HT29 and SW620, we next tried to elucidate the means by which that effect was generated. We first investigated whether or not the cells were experiencing increased apoptosis as a result of MS417 application. Flow cytometry staining with standard apoptosis markers Annexin V and PI showed minimal increases in the number of apoptotic cells (Figure 3A). Mixed results were observed through Western blotting, with Fas, an important cell surface receptor protein of the TNF receptor family, which induces apoptosis on binding Fas ligand, increased after BRD4 inhibition in both cells (Figure 3B). Interestingly, increased expression of some anti-apoptotic factors (such as XIAP) was also observed in HT29. However, the expression of XIAP decreased in SW620 (Figure 3B). It seems clear that apoptosis was not the controlling factor for BRD4-inhibition mediated suppression of the cells. This result is not surprising, given that cancer cells are generally not believed to be cleared via apoptosis.

Bottom Line: We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT).This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro.Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Road, Guangzhou 510515, China. drhuyuan@gmail.com.

ABSTRACT
Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

Show MeSH
Related in: MedlinePlus