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Theranostics 2020; 10(22):10016-10030. doi:10.7150/thno.47081 This issue Cite

Research Paper

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

Junbao Zhang1#, Ying Ying1#, Meiqi Li1#, Maolin Wang1, Xiaoyan Huang1, Min Jia1, Junhui Zeng1, Canjie Ma1, Yixiang Zhang2, Chen Li3, Xiaomei Wang1, Xing-sheng Shu1✉

1. Department of Physiology, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China.
2. Department of Urology, The Second Affiliated Hospital of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China.
3. Department of Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen 518036, China.
#These authors contributed equally to this work.

✉ Corresponding author: Dr. Xing-sheng Shu, E-mail: shuedu.cn; School of Medicine, Health Science Center, Shenzhen University, 3688 Nanhai Avenue, Shenzhen 518060, China.

Citation:
Zhang J, Ying Y, Li M, Wang M, Huang X, Jia M, Zeng J, Ma C, Zhang Y, Li C, Wang X, Shu Xs. Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer. Theranostics 2020; 10(22):10016-10030. doi:10.7150/thno.47081. https://www.thno.org/v10p10016.htm
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Abstract

Graphic abstract

Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need.

Methods: The anti-tumorigenic activity of a small-molecule inhibitor of KDM6 histone demethylases named GSK-J4 in CRC was evaluated by in vitro assays and in vivo imaging of xenografted tumors. Sphere formation, flow cytometry analysis of cell surface markers and intestinal organoid formation were performed to examine the impact of GSK-J4 on TIC properties. Transcriptome analysis and global profiling of H3K27ac, H3K27me3, and KDM6A levels by ChIP-seq were conducted to elucidate how KDM6 inhibition reshapes epigenetic landscape and thereby eliminating TICs.

Results: GSK-J4 alleviated the malignant phenotypes of CRC cells in vitro and in vivo, sensitized them to chemotherapeutic treatment, and strongly repressed TIC properties and stemness-associated gene signatures in these cells. Mechanistically, KDM6 inhibition induced global enhancer reprogramming with a preferential impact on super-enhancer-associated genes, including some key genes that control stemness in CRC such as ID1. Besides, expression of both Kdm6a and Kdm6b was more abundant in mouse intestinal crypt when compared with upper villus and inhibition of their activities blocked intestinal organoid formation. Finally, we unveiled the power of KDM6B in predicting both the overall survival outcome and recurrence of CRC patients.

Conclusions: Our study provides a novel rational strategy to eradicate TICs through reshaping epigenetic landscape in CRC, which might also be beneficial for optimizing current therapeutics.

Keywords: GSK-J4, KDM6, tumor-initiating cells, super-enhancer, colorectal cancer

Citation styles

APA
Zhang, J., Ying, Y., Li, M., Wang, M., Huang, X., Jia, M., Zeng, J., Ma, C., Zhang, Y., Li, C., Wang, X., Shu, X.s. (2020). Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer. Theranostics, 10(22), 10016-10030. https://doi.org/10.7150/thno.47081.

ACS
Zhang, J.; Ying, Y.; Li, M.; Wang, M.; Huang, X.; Jia, M.; Zeng, J.; Ma, C.; Zhang, Y.; Li, C.; Wang, X.; Shu, X.s. Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer. Theranostics 2020, 10 (22), 10016-10030. DOI: 10.7150/thno.47081.

NLM
Zhang J, Ying Y, Li M, Wang M, Huang X, Jia M, Zeng J, Ma C, Zhang Y, Li C, Wang X, Shu Xs. Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer. Theranostics 2020; 10(22):10016-10030. doi:10.7150/thno.47081. https://www.thno.org/v10p10016.htm

CSE
Zhang J, Ying Y, Li M, Wang M, Huang X, Jia M, Zeng J, Ma C, Zhang Y, Li C, Wang X, Shu Xs. 2020. Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer. Theranostics. 10(22):10016-10030.

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