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

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.

KDM6B-mediated histone demethylation of LDHA promotes lung metastasis of osteosarcoma

“…KDM6B plays a key role in the occurrence and development of various human diseases such as cancer, immune diseases and developmental diseases 15 - 18 . Targeted inhibition of KDM6 by a small-molecule inhibitor named GSK-J4 effectively eradicates tumor-initiating cells and downregulates stemness-associated gene signatures in colorectal cancer 19 . In a previous study on epigenetic regulation of drug resistance of bone tumors, histone H3K27me3 modification was found to regulate the stemness maintenance of OS tumor stem cells 20 .…”

Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types

“…Therefore, PRC2 may act as an oncogenic factor in mature hematopoietic cells while exerting tumor suppressor activities in undifferentiated or immature cells. While these tumors might be insensitive to EZH2 inhibitors, a correlation between higher expression of PRC2 and good prognosis might be of interest as it might suggest a possible sensitivity of these tumors to inhibitors of KDM6 that demethylate H3K27me3 [124], or of active chromatin components, such as those previously reported for SUZ12 inactivating mutations that sensitize several cancer types to inhibitors of Bromodomain and Extra-Terminal motif (BET) proteins, a family of proteins that counteract gene silencing with a chromatin activation function [125].…”

The JMJD Family Histone Demethylases in Crosstalk Between Inflammation and Cancer

“…At present, aiming at modulating the cancer promoting effect of JMJD3, specific small molecule inhibitors are synthesized to block the histone demethylation function of JMJD3 protein. For example, GSK-J4, a selective inhibitor of JMJD3 and UTX, has been proved to exert anticancer activity in a variety of tumor cell types, with its unique advantages of low action concentration, almost non-toxicity to normal cells, and reversible modification ( 177 – 179 ). As for colorectal cancer, Zhang J et al.…”

“…As for colorectal cancer, Zhang J et al. found that GSK-J4 can strongly inhibit the characteristics of tumor initiation cells- and stem cells- related genes in colorectal cancer, reshape the epigenetic pattern, reduce the malignant phenotype of colorectal cancer cells, and sensitize them to chemotherapy ( 179 ). In the study of prostate cancer, Cao Z et al.…”