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The KDM6A-SPARCL1 axis blocks metastasis and regulates the tumour microenvironment of gastrointestinal stromal tumours by inhibiting the nuclear translocation of p65

British Journal of Cancer volume 126, pages 1457–1469 (2022)Cite this article

Subjects

Abstract

Background

It is urgent to explore the pathogenic mechanism of gastrointestinal stromal tumours (GISTs). KDM6A, a histone demethylase, can activate gene transcription and has not been reported in GISTs. SPARCL1 may serve as a metastasis marker in GIST, but the molecular mechanism remains to be further explored. This study aimed to explore the biological function and molecular mechanism of KDM6A and SPARCL1 in GIST.

Methods

CCK-8, live cell count, colony formation, wound-healing and Transwell migration and invasion assays were employed to detect the cell proliferation, migration and invasion. A xenograft model and hepatic metastasis model were used to assess the role of KDM6A and SPARCL1 in vivo.

Results

KDM6A inhibited the proliferation, migration and invasion of GIST cells. Mechanistically, KDM6A promotes the transcription of SPARCL1 by demethylating histone H3 lysine trimethylation and consequently leads to the inactivation of p65. SPARCL1 affected the metastasis of GIST cells in a mesenchymal-epithelial transition- and matrix-metalloproteinase-dependent manner. SPARCL1 knockdown promoted angiogenesis, M2 polarisation and macrophage recruitment by inhibiting the phosphorylation of p65. Moreover, KDM6A and SPARCL1 inhibited hepatic metastasis and macrophage infiltration in vivo.

Conclusions

Our findings establish the critical role of the KDM6A-SPARCL1-p65 axis in restraining the malignancy of GIST.

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Fig. 1: KDM6A inhibits GIST-882 cell growth.
Fig. 2: KDM6A inhibits GIST cell migration, invasion and metastasis.
Fig. 3: KDM6A is downregulated in GIST tissues.
Fig. 4: SPARCL1 is a target of KDM6A.
Fig. 5: KDM6A regulates GIST cell migration and invasion by targeting SPARCL1.
Fig. 6: SPARCL1 regulates p65 phosphorylation and allocates its nuclear translocation.
Fig. 7: p65 is required for SPARCL1-induced angiogenesis in GISTs.
Fig. 8: SPARCL1 regulates M2 polarisation and macrophage recruitment via p65.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Funding

This work was supported by the Project of Science and Technology Department of Sichuan Province (No. 2020YFS0233).

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Author notes

  1. These authors contributed equally: Chaoyong Shen, Luyin Han.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China

    Chaoyong Shen, Baike Liu, Guixiang Zhang, Zhaolun Cai, Xiaonan Yin, Yuan Yin, Zhixin Chen & Bo Zhang

  2. Intensive care unit, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China

    Luyin Han

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Contributions

LYH, BKL, GXZ and ZLC contributed to conceptualisation and methodology. BKL and XNY played a key role in interpreting the results and revised the article critically for important intellectual content. XNY and YY interpreted and analysed the data. CYS, ZXC and BZ designed the work that led to the submission, acquired data, revised the manuscript, acquired funding, supervised the project and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.

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Correspondence to Bo Zhang.

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The authors declare no competing interests.

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The study was conducted in accordance with the Declaration of Helsinki. The human tissues used in this study were approved by Committees for the Ethical Review of Research at the West China Hospital, Sichuan University. We have received consent from individual patients who have participated in this study.

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Shen, C., Han, L., Liu, B. et al. The KDM6A-SPARCL1 axis blocks metastasis and regulates the tumour microenvironment of gastrointestinal stromal tumours by inhibiting the nuclear translocation of p65. Br J Cancer 126, 1457–1469 (2022). https://doi.org/10.1038/s41416-022-01728-3

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