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

Ziqing Zhan1,2, Yidong Ge1, Jiaxin Shi1

  • 1Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, China.

Cell Death & Disease
|May 9, 2026
PubMed

Insights

Hepatocellular carcinoma (HCC) cell migration is promoted by upregulated potassium-calcium-activated channel subfamily N member 3 (KCNN3). SPOP regulates KCNN3 activity, and its disruption accelerates HCC progression, offering therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Ion Channel Physiology

Background:

  • Metastasis of hepatocellular carcinoma (HCC) is a significant clinical challenge.
  • Dysregulation of ion channels, particularly K+ channels, is implicated in HCC's epithelial-mesenchymal transition (EMT).

Purpose of the Study:

  • To elucidate the role of potassium-calcium-activated channel subfamily N member 3 (KCNN3) in HCC metastasis.
  • To investigate the molecular mechanisms linking KCNN3, CCCTC-binding factor (CTCF), special AT-rich sequence-binding protein 1 (SATB1), and speckle-type POZ protein (SPOP) in HCC progression.

Main Methods:

  • Quantitative analysis of KCNN3 expression in HCC cells.
  • In vitro and in vivo assays for cell migration and invasion.
  • Western blotting and immunoprecipitation to study protein interactions and modifications.
  • Analysis of SPOP-KCNN3 ubiquitination and KCNN3 translocation.
  • Assessment of therapeutic interventions using KCNN3 inhibitors and calcium chelators.

Main Results:

  • KCNN3 ion channels are significantly upregulated in HCC cells, promoting migration and invasion.
  • KCNN3 activation enhances CTCF phosphorylation, upregulating SATB1 transcription and driving HCC cell motility.
  • Speckle-type POZ protein (SPOP) recognizes KCNN3, mediating K27-linked ubiquitination that translocates KCNN3 intracellularly, suppressing its activity.
  • HCC-associated SPOP mutations or KCNN3 alterations disrupt this regulatory axis, accelerating HCC progression.

Conclusions:

  • The KCNN3 ion channel is a key driver of HCC metastasis through the CTCF-SATB1 pathway.
  • SPOP-mediated regulation of KCNN3 activity is crucial for controlling HCC progression.
  • Targeting KCNN3 with inhibitors like edelfosine or calcium chelators presents a potential therapeutic strategy for HCC.

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