KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling

Jiong Li (), Bo Yu, Peng Deng, Yingduan Cheng, Yongxin Yu, Kareena Kevork, Sivakumar Ramadoss, Xiangming Ding, Xinmin Li and Cun-Yu Wang ()
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Jiong Li: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Bo Yu: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Peng Deng: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Yingduan Cheng: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Yongxin Yu: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Kareena Kevork: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Sivakumar Ramadoss: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA
Xiangming Ding: David Geffen School of Medicine, UCLA
Xinmin Li: David Geffen School of Medicine, UCLA
Cun-Yu Wang: Laboratory of Molecular Signaling, School of Dentistry and Broad Stem Cell Research Center, UCLA

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Human colorectal cancer stem cells (CSCs) are tumour initiating cells that can self-renew and are highly tumorigenic and chemoresistant. While genetic mutations associated with human colorectal cancer development are well-known, little is known about how and whether epigenetic factors specifically contribute to the functional properties of human colorectal CSCs. Here we report that the KDM3 family of histone demethylases plays an important role in tumorigenic potential and survival of human colorectal CSCs by epigenetically activating Wnt target gene transcription. The depletion of KDM3 inhibits tumorigenic growth and chemoresistance of human colorectal CSCs. Mechanistically, KDM3 not only directly erases repressive H3K9me2 marks, but also helps to recruit histone methyltransferase MLL1 to promote H3K4 methylation, thereby promoting Wnt target gene transcription. Our results suggest that KDM3 is a critical epigenetic factor in Wnt signalling that orchestrates chromatin changes and transcription in human colorectal CSCs, identifying potential therapeutic targets for effective elimination of CSCs.

Date: 2017
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DOI: 10.1038/ncomms15146

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