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An MST4-pβ-Catenin^Thr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis.

ABSTRACT: Elevated Wnt/β-catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4-pβ-catenin^Thr40 signaling axis essential for intestinal stem cell (ISC) homeostasis and CRC development is uncovered. In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates β-catenin at Thr40 to block its Ser33 phosphorylation by GSK3β. Thus, MST4 mediates an active process that prevents β-catenin from binding to and being degraded by β-TrCP, leading to accumulation and full activation of β-catenin. Depletion of MST4 causes loss of ISCs and inhibits CRC growth. Mice bearing either MST4^T178E mutation with constitutive kinase activity or β-catenin^T40D mutation mimicking MST4-mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4-pβ-catenin^Thr40 axis is upregulated and correlated with poor prognosis of human CRC. Collectively, this work establishes a previously undefined machinery for β-catenin activation, and further reveals its function in stem cell and tumor biology, opening new opportunities for targeted therapy of CRC.

SUBMITTER: Zhang H

PROVIDER: S-EPMC8425901 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Acute gastrointestinal syndrome (AGS) is one of the most severe clinical manifestations after exposure to high doses of radiation, and is life-threatening in radiological emergency scenarios. However, an unmet challenge is lacking of an FDA-approved drug that can ameliorate the damage of radiation-exposed intestinal tissues and accelerate the regeneration of injured epithelia. In this study, we investigated whether the small molecule Me6TREN (Me6) can regulate intestinal stem cell (ISC) proliferation and promote crypt regeneration after irradiation. Methods: Lethally irradiated mice were administered with Me6 or PBS to study the survival rate, and sections of their small intestine were subjected to immunostaining to evaluate epithelial regeneration. An intestinal organoid culture system was employed to detect the role of Me6 in organoid growth and ISC proliferation. We further investigated the key signaling pathways associated with Me6 using microarray, western blotting, and RNA interference techniques. Results: We identified the small molecule Me6 as a potent intestinal radiation countermeasure. Systemic administration of Me6 significantly improved ISC and crypt cell regeneration and enhanced the survival of mice after high doses of radiation. Using an in vitro intestinal organoid culture system, we found that Me6 not only induced ISC proliferation but also increased the budding rate of intestinal organoids under unirradiated and irradiated conditions. Me6 remarkably activated the expression of ISC-associated and proliferation-promoting genes, such as Ascl2, Lgr5, Myc, and CyclinD1. Mechanistically, Me6 strongly stimulated the phosphorylation of β-catenin at the S552 site and increased the transcriptional activity of β-catenin, a key signaling pathway for ISC self-renewal and proliferation. This is further evidenced by the fact that knockdown of β-catenin abolished the effect of Me6 on intestinal organoid growth in vitro and crypt regeneration in irradiated mice. Conclusion: The small molecule Me6TREN induced ISC proliferation, enhanced intestinal organoid growth in vitro, and promoted intestinal tissue regeneration after radiation injury by activating β-catenin signaling.

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An MST4-pβ-Catenin^Thr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis.

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Dataset Information

An MST4-pβ-CateninThr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

An MST4-pβ-Catenin^Thr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis.