Translational Therapeutics

Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner

Abstract

Background

The anticancer potential of ibuprofen has created a broad interest to explore the clinical benefits of ibuprofen in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anticancer potential of ibuprofen remains limited.

Methods

Cancer stemness assays to validate ibuprofen function in vitro and in vivo. Histone modification assays to check the effect of ibuprofen on histone acetylation/methylation, as well as the activity of HDAC and KDM6A/B. Inhibitors’ in vivo assays to evaluate therapeutic effects of various inhibitors’ combination manners.

Results

In our in vitro studies, we report that ibuprofen diminishes cancer cell stemness properties that include reducing the ALDH + subpopulation, side population and sphere formation in three cancer types. In our in vivo studies, we report that ibuprofen decreases tumour growth, metastasis and prolongs survival. In addition, our results showed that ibuprofen inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regard to the underlying molecular mechanism of action, we report that ibuprofen reduces HDACs and histone demethylase (KDM6A/B) expression that mediates histone acetylation and methylation, and suppresses gene expression via a COX2-dependent way. In regard to therapeutic strategies, we report that ibuprofen combined HDAC/HDM inhibitors prevents cancer progression in vivo.

Conclusions

The aforementioned findings suggest a molecular model that explains how ibuprofen diminishes cancer cell stemness properties. These may provide novel targets for therapeutic strategies involving ibuprofen in the prevention of cancer progression.

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Fig. 1: Ibuprofen restrains cancer cell stemness properties in vitro.
Fig. 2: Ibuprofen suppresses cancer cell metastasis and stemness in vivo.
Fig. 3: Ibuprofen inhibits the expression of inflammation-related stemness genes in vitro and in vivo.
Fig. 4: Ibuprofen mediates histone 3 methylation and acetylation to affect target genes’ expression in vitro and in vivo.
Fig. 5: Ibuprofen mediates H3 methylation and acetylation to regulate ICAM3 expression in vitro.
Fig. 6: Ibuprofen combined HDAC/HDM (KDM6A/B) inhibitors that restrained cancer progression in vivo.

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Authors

Contributions

S.W.Z., Z.X.Y. and D.R.L. designed and performed the experiments. Z.X.Y., D.R.L., G.W.J. and W.J. analysed the data. Y.W.C. and B.Y.H. provided the materials or methods for the experiment, and helped S.W.Z. to prepare the papers. L.N. and L.J.J. helped to group the figures and repaired the papers.

Corresponding authors

Correspondence to Wenzhi Shen or Na Luo or Jianjun Li.

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All animal experiments were performed in accordance with Nankai University and Jining Medical University Animal Welfare Guidelines.

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Data availability

The data are available for all study authors. The data sets used and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the National Natural Science Foundation of China (No. 81802466 to Wenzhi Shen), Faculty Start-up Funds of Jining Medical University (No. 600640001 to Wenzhi Shen), Shandong Medical Science and Technology Program (No. 2017WS144 to Wenzhi Shen) and Shandong Provincial Natural Science Foundation (No. ZR2019BH003 to Wenzhi Shen).

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Shen, W., Zhang, X., Du, R. et al. Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner. Br J Cancer 123, 730–741 (2020). https://doi.org/10.1038/s41416-020-0906-7

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