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<p>Chemoresistance remains a major barrier in colorectal cancer (CRC) therapy. Through epigenetic compound screening in patient-derived organoids (PDOs), we identified CX6258.HCl as a potent growth inhibitor. Treatment with CX6258.HCl significantly inhibited cell mitosis and induced apoptosis in CRC cell lines. Mechanistically, CX6258.HCl binds the D687 residue within HASPIN’s kinase domain, suppressing H3T3 phosphorylation (H3T3ph). This triggers an epigenetic cascade: loss of H3T3ph upregulates demethylase KDM5B pre-mRNA, depleting H3K4me3 at promoters of Kinesin family member (KIFC1/KIF10/KIF14). Consequently, microtubule dynamics are disrupted, leading to mitotic arrest. Target specificity was validated genetically <i>via</i> HASPIN-D687A mutation. In vivo, CX6258.HCl suppressed CRC xenograft growth and further enhanced 5-FU-mediated tumor suppression without obvious histological injury in major organs. Clinically, elevated H3T3ph levels in human CRC tissues were associated with Ki67-positive proliferative tumor regions, suggesting that H3T3ph may represent a proliferation-associated marker in CRC. Together, our findings identify the HASPIN/H3T3ph-KDM5B-H3K4me3-KIF axis as a targetable antimitotic pathway and support therapeutic inhibition of HASPIN/H3T3ph as a potential strategy for CRC.</p>

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Targeting HASPIN-mediated H3T3 phosphorylation disrupts an epigenetic-kinesin axis to suppress colorectal cancer mitotic progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Tong Wu,
  • Yaguang Zhang,
  • Sicheng Liu,
  • Chensong Zhang,
  • Yang Zhang,
  • Qiuye Luo,
  • Dian Gao,
  • Yang Meng,
  • Yixin Jiang,
  • Junhong Han

摘要

Chemoresistance remains a major barrier in colorectal cancer (CRC) therapy. Through epigenetic compound screening in patient-derived organoids (PDOs), we identified CX6258.HCl as a potent growth inhibitor. Treatment with CX6258.HCl significantly inhibited cell mitosis and induced apoptosis in CRC cell lines. Mechanistically, CX6258.HCl binds the D687 residue within HASPIN’s kinase domain, suppressing H3T3 phosphorylation (H3T3ph). This triggers an epigenetic cascade: loss of H3T3ph upregulates demethylase KDM5B pre-mRNA, depleting H3K4me3 at promoters of Kinesin family member (KIFC1/KIF10/KIF14). Consequently, microtubule dynamics are disrupted, leading to mitotic arrest. Target specificity was validated genetically via HASPIN-D687A mutation. In vivo, CX6258.HCl suppressed CRC xenograft growth and further enhanced 5-FU-mediated tumor suppression without obvious histological injury in major organs. Clinically, elevated H3T3ph levels in human CRC tissues were associated with Ki67-positive proliferative tumor regions, suggesting that H3T3ph may represent a proliferation-associated marker in CRC. Together, our findings identify the HASPIN/H3T3ph-KDM5B-H3K4me3-KIF axis as a targetable antimitotic pathway and support therapeutic inhibition of HASPIN/H3T3ph as a potential strategy for CRC.