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To mimic this process, ovarian cancer cells were grown in 3D and 2D culture. Hey and OVCA433 spheroids exhibited decreased cell proliferation and enhanced adhesion and invasion. SMYD3 expression was elevated in ovarian carcinoma spheroids in association with increased H3K4 methylation. Depletion of SMYD3 by transient siRNA, stable shRNA knockdown and the SMYD3 inhibitor BCI\u2010121 all decreased spheroid invasion and adhesion. Gene expression arrays revealed downregulation of integrin family members. Inhibition assays confirmed that invasion and adhesion of spheroids are mediated by ITGB6 and ITGAM. SMYD3\u2010deficient cells regained the ability to invade and adhere after forced overexpression of SMYD3, ITGB6 and ITGAM. However, this biological ability was not restored by forced overexpression of SMYD3 in ITGB6\u2010 and\/or ITGAM\u2010deficient cancer cells. SMYD3 and H3K4me3 binding at the ITGB6 and ITGAM promoters was increased in spheroids compared to that in monolayer cells, and the binding was decreased when SMYD3 expression was inhibited, consistent with the expression changes in integrins. SMYD3 expression and integrin\u2010mediated adhesion were also activated in an intraperitoneal xenograft model and in EOC patient spheroids. <jats:italic>In vivo<\/jats:italic>, SMYD3 knockdown inhibited tumor metastasis and reduced ascites volume in both the intraperitoneal xenograft model and a PDX model. Overall, our results suggest that the SMYD3\u2010H3K4me3\u2010integrin pathway plays a crucial role in ovarian cancer metastasis to the peritoneal surface.<\/jats:p>","DOI":"10.1002\/ijc.32673","type":"journal-article","created":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T14:43:23Z","timestamp":1568126603000},"page":"1553-1567","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["SMYD3 promotes implant metastasis of ovarian cancer <i>via<\/i> H3K4 trimethylation of integrin promoters"],"prefix":"10.1002","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2120-0525","authenticated-orcid":false,"given":"Tianjiao","family":"Lyu","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics Ruijin Hospital, Shanghai Jiaotong University, School of Medicine  Shanghai China"},{"name":"Department of Gynecology Obstetrics and Gynecology Hospital, Fudan University  Shanghai 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