JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway

Min Seong Kim; Hye In Cho; Hee Jung Yoon; Ye Hyeon Ahn; Eun Jung Park; Yan Hua Jin; Yeun Kyu Jang

doi:10.1038/s41598-018-24903-0

JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway

Min Seong Kim, Hye In Cho, Hee Jung Yoon, Ye Hyeon Ahn, Eun Jung Park, Yan Hua Jin, Yeun Kyu Jang

Department of Systems Biology

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

Abstract

Although several epigenetic modulating drugs are suggested to target cancer stem cells (CSCs), additional identification of anti-CSC drugs is still necessary. Here we showed that JIB-04, a pan-selective inhibitor of histone demethylase(s), was identified as a small molecule that selectively target colorectal CSCs. Our data showed that JIB-04 is capable of reducing self-renewal and stemness of colorectal CSCs in three different colorectal cancer cell lines. JIB-04 significantly attenuated CSC tumorsphere formation, growth/relapse, invasion, and migration in vitro. Furthermore, JIB-04-treated colorectal cancer cells showed reduced tumorigenic activity in vivo. RNA sequencing analysis revealed that JIB-04 affected various cancer-related signaling pathways, especially Wnt/β-catenin signaling, which is crucial for the proliferation and maintenance of colorectal cancer cells. qRT-PCR and TOP/FOP flash luciferase assays showed that JIB-04 down-regulated the expression of Wnt/β-catenin-regulated target genes associated with colorectal CSC function. Overall, the effects of JIB-04 were equal to or greater than those of salinomycin, a known anti-colorectal CSC drug, despite the lower concentration of JIB-04 compared with that of salinomycin. Our results strongly suggest that JIB-04 is a promising drug candidate for colorectal cancer therapy.

Original language	English
Article number	6611
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-24903-0
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding Information:
The authors thank all faculty members in Department of Systems Biology for their encouragement. Specially, the authors thank JooHun Lee, Tae Ho Lee, In Kwon Chung, Jihyun F. Kim, Hyun-Soo Cho, and Kwang-Min Choe for key insights, support and helpful advice. This work was supported in part by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) [No. 2011-0030049] and partly by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future Planning [No. 2016R1A2B1012050]. In addition, M.S.K., H.I.C., and Y.K.J. were supported in part by the Brain Korea 21 (BK21) PLUS program. In addition, this research was partly supported by National Natural Science Foundation of China (No. 81660494). This research was in part supported by the Graduate School of YONSEI University Research Scholarship Grants in 2017 (to H.I.C.).

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© 2018 The Author(s).

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title = "JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway",

abstract = "Although several epigenetic modulating drugs are suggested to target cancer stem cells (CSCs), additional identification of anti-CSC drugs is still necessary. Here we showed that JIB-04, a pan-selective inhibitor of histone demethylase(s), was identified as a small molecule that selectively target colorectal CSCs. Our data showed that JIB-04 is capable of reducing self-renewal and stemness of colorectal CSCs in three different colorectal cancer cell lines. JIB-04 significantly attenuated CSC tumorsphere formation, growth/relapse, invasion, and migration in vitro. Furthermore, JIB-04-treated colorectal cancer cells showed reduced tumorigenic activity in vivo. RNA sequencing analysis revealed that JIB-04 affected various cancer-related signaling pathways, especially Wnt/β-catenin signaling, which is crucial for the proliferation and maintenance of colorectal cancer cells. qRT-PCR and TOP/FOP flash luciferase assays showed that JIB-04 down-regulated the expression of Wnt/β-catenin-regulated target genes associated with colorectal CSC function. Overall, the effects of JIB-04 were equal to or greater than those of salinomycin, a known anti-colorectal CSC drug, despite the lower concentration of JIB-04 compared with that of salinomycin. Our results strongly suggest that JIB-04 is a promising drug candidate for colorectal cancer therapy.",

author = "Kim, {Min Seong} and Cho, {Hye In} and Yoon, {Hee Jung} and Ahn, {Ye Hyeon} and Park, {Eun Jung} and Jin, {Yan Hua} and Jang, {Yeun Kyu}",

note = "Funding Information: The authors thank all faculty members in Department of Systems Biology for their encouragement. Specially, the authors thank JooHun Lee, Tae Ho Lee, In Kwon Chung, Jihyun F. Kim, Hyun-Soo Cho, and Kwang-Min Choe for key insights, support and helpful advice. This work was supported in part by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) [No. 2011-0030049] and partly by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future Planning [No. 2016R1A2B1012050]. In addition, M.S.K., H.I.C., and Y.K.J. were supported in part by the Brain Korea 21 (BK21) PLUS program. In addition, this research was partly supported by National Natural Science Foundation of China (No. 81660494). This research was in part supported by the Graduate School of YONSEI University Research Scholarship Grants in 2017 (to H.I.C.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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T1 - JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway

AU - Kim, Min Seong

AU - Cho, Hye In

AU - Yoon, Hee Jung

AU - Ahn, Ye Hyeon

AU - Park, Eun Jung

AU - Jin, Yan Hua

AU - Jang, Yeun Kyu

N1 - Funding Information: The authors thank all faculty members in Department of Systems Biology for their encouragement. Specially, the authors thank JooHun Lee, Tae Ho Lee, In Kwon Chung, Jihyun F. Kim, Hyun-Soo Cho, and Kwang-Min Choe for key insights, support and helpful advice. This work was supported in part by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) [No. 2011-0030049] and partly by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future Planning [No. 2016R1A2B1012050]. In addition, M.S.K., H.I.C., and Y.K.J. were supported in part by the Brain Korea 21 (BK21) PLUS program. In addition, this research was partly supported by National Natural Science Foundation of China (No. 81660494). This research was in part supported by the Graduate School of YONSEI University Research Scholarship Grants in 2017 (to H.I.C.). Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Although several epigenetic modulating drugs are suggested to target cancer stem cells (CSCs), additional identification of anti-CSC drugs is still necessary. Here we showed that JIB-04, a pan-selective inhibitor of histone demethylase(s), was identified as a small molecule that selectively target colorectal CSCs. Our data showed that JIB-04 is capable of reducing self-renewal and stemness of colorectal CSCs in three different colorectal cancer cell lines. JIB-04 significantly attenuated CSC tumorsphere formation, growth/relapse, invasion, and migration in vitro. Furthermore, JIB-04-treated colorectal cancer cells showed reduced tumorigenic activity in vivo. RNA sequencing analysis revealed that JIB-04 affected various cancer-related signaling pathways, especially Wnt/β-catenin signaling, which is crucial for the proliferation and maintenance of colorectal cancer cells. qRT-PCR and TOP/FOP flash luciferase assays showed that JIB-04 down-regulated the expression of Wnt/β-catenin-regulated target genes associated with colorectal CSC function. Overall, the effects of JIB-04 were equal to or greater than those of salinomycin, a known anti-colorectal CSC drug, despite the lower concentration of JIB-04 compared with that of salinomycin. Our results strongly suggest that JIB-04 is a promising drug candidate for colorectal cancer therapy.

AB - Although several epigenetic modulating drugs are suggested to target cancer stem cells (CSCs), additional identification of anti-CSC drugs is still necessary. Here we showed that JIB-04, a pan-selective inhibitor of histone demethylase(s), was identified as a small molecule that selectively target colorectal CSCs. Our data showed that JIB-04 is capable of reducing self-renewal and stemness of colorectal CSCs in three different colorectal cancer cell lines. JIB-04 significantly attenuated CSC tumorsphere formation, growth/relapse, invasion, and migration in vitro. Furthermore, JIB-04-treated colorectal cancer cells showed reduced tumorigenic activity in vivo. RNA sequencing analysis revealed that JIB-04 affected various cancer-related signaling pathways, especially Wnt/β-catenin signaling, which is crucial for the proliferation and maintenance of colorectal cancer cells. qRT-PCR and TOP/FOP flash luciferase assays showed that JIB-04 down-regulated the expression of Wnt/β-catenin-regulated target genes associated with colorectal CSC function. Overall, the effects of JIB-04 were equal to or greater than those of salinomycin, a known anti-colorectal CSC drug, despite the lower concentration of JIB-04 compared with that of salinomycin. Our results strongly suggest that JIB-04 is a promising drug candidate for colorectal cancer therapy.

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JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway

Abstract

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