SPOP-mediated K27-linked non-degradative ubiquitination of KCNN3 suppressing HCC progression via the CTCF-SATB1 axis.

Authors

Ziqing Zhan, Yidong Ge, Jiaxin Shi, Hongze Liang, Yuxuan Li, Jiabei Jin, Gun Chen, Fengguang Zhai, Lili Kong, Yan Lin, Siyuan Wang, Litao Chen, Linlin Liu, Kuihao Chen, Pengrong Lou, Meng Ye, Xiaofeng Jin

Published in

Cell death & disease. Volume 17. Issue 1. May 10, 2026. Epub May 10, 2026.

Abstract

The metastasis of hepatocellular carcinoma (HCC) cells remains a major obstacle to achieving favorable clinical outcomes, yet the underlying molecular mechanisms are still not fully understood. 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 "CCCTC" 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 "ASSTT" (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-ΔSBC dramatically disrupt the SPOP-KCNN3 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.

PMID:
42106340
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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