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The dysregulation of ion channels is related to epithelial-mesenchymal transition (EMT) phenotype-related pathways, especially the aberrant function of K+ ion channels in HCC. In this study, we observed that the potassium-calcium-activated channel subfamily N member 3 (KCNN3\/SK3\/ KCa2.3) ion channels were significantly upregulated in HCC cells, promoting the migration and invasion of HCC in vitro and in vivo. Mechanistically, activation of the KCNN3 ion channel was found to enhance phosphorylation of the CCCTC-binding factor (CTCF), which in turn stimulates transcription of the EMT-related factor special AT-rich sequence-binding protein 1 (SATB1) via binding the \u201cCCCTC\u201d region within its promoter, thereby driving HCC cell migration and invasion. Furthermore, we identified that speckle-type POZ protein (SPOP), an E3 ligase adaptor, recognizes the SPOP-binding consensus (SBC) motif \u201cASSTT\u201d (aa 250-254) in KCNN3 and mediates its ubiquitination via K27-linked ubiquitin chain. Notably, this type of ubiquitination does not induce KCNN3 turnover, but induced KCNN3 translocation from the cell membrane into the cytosol, thus suppressing KCNN3-mediated ion channel activity. Importantly, HCC-associated SPOP mutations or KCNN3-\u0394SBC dramatically disrupt the SPOP\u2013KCNN3 regulatory axis, accelerating HCC progression. These effects can be effectively counteracted by treatment with the KCNN3 channel inhibitor edelfosine and the calcium chelators BAPTA-AM, suggesting a promising therapeutic strategy for HCC patients.<\/jats:p>","DOI":"10.1038\/s41419-026-08765-3","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:43:45Z","timestamp":1778373825000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SPOP-mediated K27-linked non-degradative ubiquitination of KCNN3 suppressing HCC progression via the CTCF-SATB1 axis"],"prefix":"10.1038","volume":"17","author":[{"given":"Ziqing","family":"Zhan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0964-0293","authenticated-orcid":false,"given":"Yidong","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8278-2258","authenticated-orcid":false,"given":"Hongze","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengguang","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Litao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2738-7762","authenticated-orcid":false,"given":"Kuihao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9676-5875","authenticated-orcid":false,"given":"Pengrong","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5827-3704","authenticated-orcid":false,"given":"Meng","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0801-8638","authenticated-orcid":false,"given":"Xiaofeng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"8765_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-014-0394-0","volume":"16","author":"O Abdel-Rahman","year":"2014","unstructured":"Abdel-Rahman O. 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