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.
Highlights
Human colorectal cancer stem cells (CSCs) are tumour initiating cells that can self-renew and are highly tumorigenic and chemoresistant
In addition to erasing H3K9me[2] marks, we find that that KDM3 facilitate PYGO2 and B-cell lymphoma 9 (BCL9) binding to chromatin by histone methyltransferase mixed lineage leukaemia 1 (MLL1)-mediated H3K4 methylation
We found that the knockdown of the KDM3 family histone demethylases inhibited Topflash luciferase activities induced by LiCl in human embryonic kidney 293 T cells expressing a T cell factors (Tcfs)-responsive Topflash reporter (293 T/Top) (Fig. 1a)
Summary
Real-time RT-PCR indicated that the depletion of KDM3A/B significantly inhibits the expression of Wnt target genes in ALDH þ HCT116 cells (Fig. 3b). The depletion of KDM3A/B significantly reduced the expression of Wnt target genes (Supplementary Fig. 3f), and abolished the tumorsphere formation ability of ALDH þ SW480 cells (Supplementary Fig. 3g). We found that the depletion of KDM3A/B in CSCs isolated from human CRC tissues of the patient in case 2 inhibited tumorsphere formation in vitro and tumour formation in vivo by inhibiting Wnt/b-catenin signalling (Supplementary Fig. 3d–g). Knockdown of KDM3A/B significantly inhibited the expression of Wnt target genes in ALDH þ cells isolated from HCP1 cells (Fig. 4i). The restoration of KDM4B expression in KDM3A/B knockdown ALDH þ HCT116 cells significantly restored cell resistance to cisplatin and irinotecan (Supplementary Fig. 4d). Western blot found that the knockdown of KDM3A/B increased caspase-3 activities and cleavage of PARP-1
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