Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells

Abstract

In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog ( IHH ), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.

TRIM25 Regulates Oxaliplatin Resistance in Colorectal Cancer by Promoting EZH2 Stability

“…As the catalytic subunit of PRC2, EZH2 plays an essential role in tumor progression. Previous study has revealed that targeting EZH2 inhibits CSC self-renewal and enhances the sensitivity of CRC to OXA [13][14]. In the present study, we found that knockdown of TRIM25 decreased the protein level of EZH2 (Fig.…”

“…Previous studies have identi ed the driving role of EZH2 in stem cell self-renewal. In CRC, EZH2 functions as a transcriptional repressor to downregulate IHH, a key gene responsible for normal colonocyte differentiation, resulting in improvement of self-renewal capacity of CSC [14]; in breast cancer, EZH2 increases NOTCH1 expression by directly binding to the NOTCH1 promoter and further promotes CSC properties or expands CSCs [16]. Besides its canonical function via regulation of H3K27me3, EZH2 is reported to increase the self-renewal capacity of CSC through binding to some non-histone targets, such as STAT3, NF-kB and β-catenin [31][32][33].…”

“…It has been shown that EZH2 is associated with a high proliferation rate, aggressive tumor subtypes, and poor outcome of cancer patients [12]. Besides, EZH2 is reported to contribute to chemotherapy response, and EZH2 inhibitors have been proved to reverse drug-resistance in cancers [13,14]. Recent studies showed that EZH2 plays an essential role in maintaining CSC properties in multiple cancer types including breast cancer, prostate cancer and glioblastoma [15][16][17].…”

“…Recent studies showed that EZH2 plays an essential role in maintaining CSC properties in multiple cancer types including breast cancer, prostate cancer and glioblastoma [15][16][17]. In the context of CRC, EZH2 has been proved to contribute to the CSC state by modulating key pathways such as Wnt/βcatenin and Hedgehog signaling, where high activity has been shown to designate the CSC population [14]. Therefore, EZH2 might be a promising target for cancer therapy.…”

Comprehensive analysis of lncRNAs reveals candidate prognostic biomarkers in multiple cancer types

“…NHEJ1 is a core component of the non-homologous end joining (NHEJ) pathway that conducts DNA double strand break repair and maintains genome stability [39, 40]. Indian hedgehog (IHH) signaling regulates differentiation of colonocytes while epigenetic activation of IHH causes decreased self-renewal of colorectal cancer-initiating cells and increased sensitivity to chemotherapy [41][42]. We speculate that the prognostic lncRNA AC097468.7 is involved in the regulation of these pathways through interactions with adjacent protein-coding genes.…”