What question did this study set out to answer?

The aim was to explore how zeylenone affects tamoxifen resistance in breast cancer cells and the involved mechanisms.

March 12, 2026

Zeylenone Attenuates Tamoxifen Resistance by Directly Binding to CTCF and Inhibiting the CTCF‐CENPK‐JAK1/STAT3 Signaling Axis in Breast Cancer

Key Points

The aim was to explore how zeylenone affects tamoxifen resistance in breast cancer cells and the involved mechanisms.
In vitro assays on MCF-7/TAM cells to assess proliferation and apoptosis.
Molecular docking analyses to evaluate zeylenone's binding to CTCF.
ChIP-qPCR and luciferase assays to study CTCF's regulatory role on CENPK.
In vivo experiments using nude mice to observe tumor growth.
Pathway analysis for JAK1/STAT3 signaling modulation.
Zeylenone downregulated CTCF and CENPK expression in a dose- and time-dependent manner.
Knockdown of CENPK suppressed cell proliferation and promoted apoptosis.
Zeylenone binding to CTCF inhibited its regulation of CENPK, impacting the JAK1/STAT3 pathway.
Overexpression of CTCF reduced the effectiveness of zeylenone in overcoming tamoxifen resistance.
This study establishes a functional regulatory axis linking CTCF and CENPK in tamoxifen resistance.

Abstract

This study was designed to investigate the effects of zeylonone (Zey) on attenuating tamoxifen (TAM) resistance in breast cancer cells in vitro and in vivo and its underlying mechanisms. Database analysis and clinical sample validation revealed that CENPK is significantly upregulated in breast cancer tissues and TAM-resistant cells, and its expression positively correlates with CTCF mRNA levels. Knockdown of CENPK markedly suppressed proliferation and colony formation, induced G0/G1 cell cycle arrest, promoted apoptosis in MCF-7/TAM cells, and inhibited tumor growth in nude mice, thereby attenuating TAM resistance. Zey treatment resulted in dose- and time-dependent downregulation of both CTCF and CENPK at the protein and mRNA levels. Molecular docking provided preliminary computational evidence suggesting Zey can bind to CTCF (binding energy:-6.9 kcal/mol), with subsequent biophysical and functional assays supporting this interaction, and thermal shift assays demonstrated that Zey enhances the thermal stability of CTCF. ChIP-qPCR and luciferase reporter assays confirmed that CTCF directly binds to the CENPK promoter and positively regulates its transcription, and Zey inhibits this regulatory process by directly binding to CTCF. Mechanistically, the CTCF/CENPK axis is associated with JAK1/STAT3 pathway modulation (increasing phosphorylation levels of JAK1 and STAT3), and Zey significantly reduces pathway activity by suppressing this axis. Overexpression of CTCF attenuated the anti-resistance effects of Zey, whereas knockdown of CENPK or JAK1 restored Zey's efficacy. While CTCF and CENPK have been individually implicated in cancer progression, this study provides the first evidence linking them in a functional regulatory axis that drives tamoxifen resistance. Zey attenuates tamoxifen resistance in breast cancer cells by directly binding to CTCF, thereby inhibiting CTCF-mediated transcriptional regulation of CENPK, downregulating CENPK expression, and subsequently suppressing the JAK1/STAT3 signaling pathway.

Bookmark

Cite This Study

Li et al. (Sun,) studied this question.

synapsesocial.com/papers/69b258a396eeacc4fcec8749 https://doi.org/https://doi.org/10.1002/ddr.70255

Bookmark