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

Tong Wu1, Yaguang Zhang1, Sicheng Liu1

  • 1Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, State Key Laboratory of Biotherapy and Cancer Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.

Molecular Cancer
|July 7, 2026
PubMed

Insights

A new drug, CX6258.HCl, effectively inhibits colorectal cancer (CRC) growth by targeting the HASPIN pathway. This epigenetic approach suppresses mitosis and enhances chemotherapy, offering a promising new strategy for CRC treatment.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Chemoresistance is a significant challenge in colorectal cancer (CRC) treatment.
  • Epigenetic modifications play a crucial role in cancer progression and drug resistance.

Purpose of the Study:

  • To identify novel therapeutic targets and agents for colorectal cancer (CRC) by screening epigenetic compounds.
  • To investigate the mechanism of action of CX6258.HCl in inhibiting CRC growth and overcoming chemoresistance.

Main Methods:

  • Screening of epigenetic compounds using patient-derived organoids (PDOs).
  • In vitro studies on CRC cell lines to assess cytotoxicity, apoptosis, and cell cycle effects.
  • Mechanistic studies involving protein binding assays, Western blotting, and genetic validation (HASPIN-D687A mutation).
  • In vivo studies using CRC xenograft models and combination therapy with 5-FU.
  • Clinical correlation analysis of H3T3ph levels in human CRC tissues.

Main Results:

  • CX6258.HCl identified as a potent inhibitor of CRC cell growth, inducing apoptosis and mitotic arrest.
  • CX6258.HCl targets HASPIN at the D687 residue, suppressing H3T3 phosphorylation (H3T3ph).
  • This leads to KDM5B upregulation, H3K4me3 depletion, and disruption of microtubule dynamics via KIFs.
  • CX6258.HCl demonstrated efficacy in vivo, suppressing xenograft growth and potentiating 5-FU therapy.
  • Elevated H3T3ph levels correlate with tumor proliferation (Ki67) in human CRC.

Conclusions:

  • The HASPIN/H3T3ph-KDM5B-H3K4me3-KIF axis represents a novel, targetable antimitotic pathway in CRC.
  • Therapeutic inhibition of HASPIN/H3T3ph is a potential strategy for overcoming CRC chemoresistance.
  • H3T3ph may serve as a predictive biomarker for tumor proliferation in CRC.
Keywords:
CX6258.HClColorectal cancerH3T3phKDM5BMitosisOrganoid

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