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Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers [LOVO sgTLE4]

ABSTRACT: Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE265907 | GEO | 2024/07/22

REPOSITORIES: GEO

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Project description:Regeneration capacity of intestinal epithelial cells are highly dependent on the status of stemness. In the homeostasis, only a small subset of stem cells is responsible for the turnover of the intestinal epithelium. However, at the injury, such as caused by radiation, intestinal epithelial cells show substantial plasticity for regeneration. Most of the colorectal cancers (CRCs) are differentiated adenocarcinoma, which maintain the expression of both stemness and differentiation markers, suggesting an existence of a similar regeneration system as in normal cells, although the role of such fluctuation of stemness in regeneration of cancer after irradiation is not well understood. In the present study, we first examined the effect of radiation on growth, stemness and differentiation using organoids derived from differentiated CRC. Both proliferation and stemness markers were once drastically decreased after sub-lethal dose of irradiation, meanwhile differentiation markers remained. After the static phase, regrowth foci consisting of proliferating cells with expression of the stem cell markers reappeared. We applied the foci formation to a radio-sensitivity assay in CRC organoids. Radio-sensitivity, the ability of foci formation, differed among the examined lines, and correlated well with the in vivo radiation sensitivity. The radio-sensitivity decreased after mechanical disruption of the organoids, which we have reported to increase the stemness of CRC organoids in a WNT dependent manner. Pre-treatment of organoids with histone deacetylase inhibitors increased radiation sensitivity, accompanied with suppressed expression of WNT target genes, and WNT inhibitors increased radio-sensitivity, suggesting that not all but some of the cancer cells with high WNT activity at the timing of radiation is the origin of the foci formation. The radiation sensitivity assay using CRC organoids established in the present study would provide a novel platform to evaluate the radiosensitizers against differentiated adenocarcinoma of CRC.

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Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers [LOVO sgTLE4]

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