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

• Published in: British journal of cancer 2022-06, Vol.126 (10), p.1457-1469
• Main Authors: Shen, Chaoyong, Han, Luyin, Liu, Baike, Zhang, Guixiang, Cai, Zhaolun, Yin, Xiaonan, Yin, Yuan, Chen, Zhixin, Zhang, Bo
• Format: Article
• Language: English
• Subjects: 631/250; 692/4028/67/1504; Angiogenesis; Animals; Biomedical and Life Sciences; Biomedicine; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cancer Research; Cell Line, Tumor; Cell Proliferation; Cholecystokinin; Digestive system; Drug Resistance; Epidemiology; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Gastrointestinal cancer; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - pathology; Gene Expression Regulation, Neoplastic; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histone H3; Histones; Humans; Leukocyte migration; Liver; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Lysine; Macrophages; Malignancy; Matrix metalloproteinase; Mesenchyme; Metalloproteinase; Metastases; Metastasis; Methylation; Microenvironments; Molecular Medicine; Nuclear transport; Oncology; Phosphorylation; Tumor Microenvironment; Tumors; Wound healing; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-01728-3

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.