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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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BRD4 inhibition suppresses CRC liver metastasis in vivo. (A,B) Macroscopic images of resected livers at the conclusion of the experiment in mice injected by HT29 or SW620 cell lines and then treated by vehicle/MS417 (20 mg/kg, n = 5/treatment); (C,D) Representative microscopic H&E images of livers. Metastatic focus is circled. ***p < 0.001. Values are depicted as Mean ± SEM.
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ijms-16-01928-f005: BRD4 inhibition suppresses CRC liver metastasis in vivo. (A,B) Macroscopic images of resected livers at the conclusion of the experiment in mice injected by HT29 or SW620 cell lines and then treated by vehicle/MS417 (20 mg/kg, n = 5/treatment); (C,D) Representative microscopic H&E images of livers. Metastatic focus is circled. ***p < 0.001. Values are depicted as Mean ± SEM.

Mentions: Liver metastasis commonly occurs in conjunction with CRC, and is obviously highly detrimental. It was also a natural extension of our investigation, given that metastasis requires EMT and intracellular communication. Based on the promising effect BRD4 inhibition had on curtailing the migration and invasion of colon cancer cell lines in vitro and our results indicating changes it induced in EMT, we next used a liver metastasis model to further confirm our results in vivo using HT29 and SW620 cells. BRD4 inhibitor MS417 was administered by intraperitoneal injection every two days, starting two days after tumor cell inoculation into the spleen. After three weeks, all of the mice injected with SW620 developed liver tumors. In the HT29 group however, only 40% of the mice treated with MS417 exhibited liver metastasis, while all of the ones treated with sham (DMSO) developed tumors (Figure 5A,B). Both cell lines showed significant inhibition of metastatic capability with the number of metastases in liver dropping by over an order of magnitude, and fewer liver micrometastases per liver section, following BRD4 inhibition (Figure 5C,D). This result was somewhat unsurprising, since tumor metastasis relies on significant intercellular communication and signal propagation. The complete blockage of metastasis of HT29 in some mice treated with BRD4 inhibitor clarifies the need for BRD4 in EMT. Collectively, these results further support our hypothesis that the in vitro effect of EMT and signaling suppression following BRD4 inhibition is also present in vivo.


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 suppresses CRC liver metastasis in vivo. (A,B) Macroscopic images of resected livers at the conclusion of the experiment in mice injected by HT29 or SW620 cell lines and then treated by vehicle/MS417 (20 mg/kg, n = 5/treatment); (C,D) Representative microscopic H&E images of livers. Metastatic focus is circled. ***p < 0.001. Values are depicted as Mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-01928-f005: BRD4 inhibition suppresses CRC liver metastasis in vivo. (A,B) Macroscopic images of resected livers at the conclusion of the experiment in mice injected by HT29 or SW620 cell lines and then treated by vehicle/MS417 (20 mg/kg, n = 5/treatment); (C,D) Representative microscopic H&E images of livers. Metastatic focus is circled. ***p < 0.001. Values are depicted as Mean ± SEM.
Mentions: Liver metastasis commonly occurs in conjunction with CRC, and is obviously highly detrimental. It was also a natural extension of our investigation, given that metastasis requires EMT and intracellular communication. Based on the promising effect BRD4 inhibition had on curtailing the migration and invasion of colon cancer cell lines in vitro and our results indicating changes it induced in EMT, we next used a liver metastasis model to further confirm our results in vivo using HT29 and SW620 cells. BRD4 inhibitor MS417 was administered by intraperitoneal injection every two days, starting two days after tumor cell inoculation into the spleen. After three weeks, all of the mice injected with SW620 developed liver tumors. In the HT29 group however, only 40% of the mice treated with MS417 exhibited liver metastasis, while all of the ones treated with sham (DMSO) developed tumors (Figure 5A,B). Both cell lines showed significant inhibition of metastatic capability with the number of metastases in liver dropping by over an order of magnitude, and fewer liver micrometastases per liver section, following BRD4 inhibition (Figure 5C,D). This result was somewhat unsurprising, since tumor metastasis relies on significant intercellular communication and signal propagation. The complete blockage of metastasis of HT29 in some mice treated with BRD4 inhibitor clarifies the need for BRD4 in EMT. Collectively, these results further support our hypothesis that the in vitro effect of EMT and signaling suppression following BRD4 inhibition is also present in vivo.

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