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Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer

Abstract

In many cancers, tumour progression is associated with increased tissue stiffness. Yet, the mechanisms associating tissue stiffness with tumorigenesis and malignant transformation are unclear. Here we show that in gastric cancer cells, the stiffness of the extracellular matrix reversibly regulates the DNA methylation of the promoter region of the mechanosensitive Yes-associated protein (YAP). Reciprocal interactions between YAP and the DNA methylation inhibitors GRHL2, TET2 and KMT2A can cause hypomethylation of the YAP promoter and stiffness-induced oncogenic activation of YAP. Direct alteration of extracellular cues via in situ matrix softening reversed YAP activity and the epigenetic program. Our findings suggest that epigenetic reprogramming of the mechanophysical properties of the extracellular microenvironment of solid tumours may represent a therapeutic strategy for the inhibition of cancer progression.

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Fig. 1: Molecular regulation of mechanotransducing YAP in gastric cancer.
Fig. 2: Effects of matrix modulation on mechanotransduction signalling and YAP activation.
Fig. 3: Time-dependent recovery effect of matrix rigidity alteration on YAP activity.
Fig. 4: Effect of transcriptional YAP silencing on matrix stiffness-mediated YAP activity.
Fig. 5: Effects of DNA methylation inhibitors on mechanosensitive YAP activation.

Data availability

The data used to make the figures are available as Supplementary Information. Web links to publicly available transcriptomic datasets are provided in the Methods. All of the sequence data have been deposited to the NCBI Sequence Read Archive with the BioProject ID PRJNA673653 and SRP accession code SRP290642. Raw data are available from the corresponding authors upon reasonable request.

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Acknowledgements

This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2019R1A2C2084142 to P.K.), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI14C1324 to P.K. and J.-H.C.). This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation of Korea, funded by the Ministry of Science and ICT (NRF-2017M3A9A7050612 to J.K.C.).

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Authors and Affiliations

Authors

Contributions

M.J. and P.K. designed the experiments. M.J. and S.W.O. performed the experiments and analysed the data. J.A., M.J. and J.K.C. performed the bioinformatics analysis. J.Y.L. and J.-H.C. helped with approval of the Institutional Review Board at the Yonsei University Severance Hospital and executed clinical applications. J.K. helped with the YAP depletion experiments. M.J., J.A., J.K.C., J.-H.C. and P.K. wrote the manuscript. All authors discussed the results and reviewed the manuscript.

Corresponding authors

Correspondence to Jung Kyoon Choi, Jae-Ho Cheong or Pilnam Kim.

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The authors declare no competing interests.

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Peer review information Nature Biomedical Engineering thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–13 and Table 1.

Reporting Summary

Supplementary Data 1

Source data for the figures.

Supplementary Video 1

Snapshots of AGS cells in the stiff matrix, captured every 12 h over the course of 72 h.

Supplementary Video 2

Snapshots of AGS cells in the softened matrix, captured every 12 h over the course of 72 h.

Supplementary Video 3

Snapshots of AGS cells in the soft matrix, captured every 12 h over the course of 72 h.

Supplementary Video 4

Snapshots of AGS cells under control siRNA treatment in the stiff matrix, captured every 12 h over the course of 72 h.

Supplementary Video 5

Snapshots of AGS cells under control siRNA treatment in the soft matrix, captured every 12 h over the course of 72 h.

Supplementary Video 6

Snapshots of YAP-depleted AGS cells under siYAP treatment in the stiff matrix, captured every 12 h over the course of 72 h.

Supplementary Video 7

Snapshots of YAP-depleted AGS cells under siYAP treatment in the soft matrix, captured every 12 h over the course of 72 h.

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Jang, M., An, J., Oh, S.W. et al. Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer. Nat Biomed Eng 5, 114–123 (2021). https://doi.org/10.1038/s41551-020-00657-x

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