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EZH2 depletion blocks the proliferation of colon cancer cells.

ABSTRACT: The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi)-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer.

SUBMITTER: Fussbroich B

PROVIDER: S-EPMC3135584 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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EZH2 depletion blocks the proliferation of colon cancer cells.

Fussbroich Bettina B Wagener Nina N Macher-Goeppinger Stephan S Benner Axel A Fälth Maria M Sültmann Holger H Holzer Angela A Hoppe-Seyler Karin K Hoppe-Seyler Felix F

PloS one 20110713 7

The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi)-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfect ...[more]

PMID: 21765901

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Project description:BackgroundResearch has indicated that the emergence of Schwann cells around premalignant lesions of colon cancer might be an early indicator promoting the onset of tumorigenesis. The present study explored the communication between colon cancer cells and Schwann cells.MethodsImmunofluorescence analyses were conducted to examine the differential distribution of Schwann cells within colon cancer tissues and normal colon tissues. CCK8 assay, colony formation assay, wound healing assay, and transwell assay were performed to investigate the interaction between colon cancer cells and Schwann cells. Exosomes derived from colon cancer cells were isolated to further explore the effect of colon cancer cells on Schwann cells. Gain- and loss-of function experiments, luciferase reporter assays, chromatin immunoprecipitation assays, and immunohistochemistry assays were performed to reveal the cross-talk between colon cancer cells and Schwann cells. Furthermore, colon cancer cells co-cultured with Schwann cells were transplanted into nude mice for evaluating their effect on tumor proliferation and metastasis in vivo.ResultsThe clinicopathological characteristics indicated that Schwann cells were enriched in colon cancer tissues and were associated with tumor metastasis and poor prognosis. The co-culture of Schwann cells with colon cancer cells promoted the proliferation and migration of colon cancer cells and Schwann cells, which was mediated by nerve growth factor (NGF) secreted from Schwann cells. Exosomal miR-21-5p released by colon cancer cells inhibited VHL expression in Schwann cells, which in turn stabilized the HIF-1α protein and increased the transcription of NGF. Meanwhile, the Schwann cells-derived NGF activated TrkA/ERK/ELK1/ZEB1 signaling pathway in colon cancer cells, which further enhanced the expression of exosomal miR-21-5p. Inhibition of either NGF or miR-21-5p significantly inhibited the proliferation and metastasis of transplanted colon cancer cells in nude mice. Coincidently, miR-21-5p was positively associated with the expression of NGF, p-ERK, p-ELK1, and ZEB1 in human colon cancer tissues.ConclusionsOur results implicated a reciprocal communication between colon cancer cells and Schwan cells that promoted the proliferation and metastasis of colon cancer, and identified NGF and exosomal miR-21-5p as potential therapeutic targets for the treatment of colon cancer.

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EZH2 depletion blocks the proliferation of colon cancer cells.

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EZH2 depletion blocks the proliferation of colon cancer cells.

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