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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月10日

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  • 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

摘要

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.