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

IF 42.2 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2026-07-07 DOI:10.1186/s12943-026-02723-5

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

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Abstract

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.

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靶向haspin介导的H3T3磷酸化破坏表观遗传-激酶轴抑制结直肠癌有丝分裂进程。

化疗耐药仍然是结直肠癌（CRC）治疗的主要障碍。通过对患者源性类器官（PDOs）的表观遗传化合物筛选，我们确定了CX6258。盐酸是一种有效的生长抑制剂。CX6258处理。盐酸显著抑制结直肠癌细胞系细胞有丝分裂，诱导细胞凋亡。从力学上看,CX6258。HCl结合HASPIN激酶结构域内的D687残基，抑制H3T3磷酸化（H3T3ph）。这触发了一个表观遗传级联：H3T3ph的缺失上调了去甲基化酶KDM5B前mrna，耗尽了激酶家族成员（KIFC1/KIF10/KIF14）的H3K4me3启动子。因此，微管动力学被破坏，导致有丝分裂停止。通过HASPIN-D687A突变基因验证靶特异性。在体内，CX6258。HCl抑制结直肠癌异种移植物生长，并进一步增强5- fu介导的肿瘤抑制作用，在主要器官无明显组织学损伤。临床发现，人结直肠癌组织中H3T3ph水平升高与ki67阳性的增生性肿瘤区域相关，提示H3T3ph可能是结直肠癌中增殖相关的标志物。总之，我们的研究结果确定了HASPIN/H3T3ph- kdm5b - h3k4me3 - kif轴是一个可靶向的抗有丝分裂途径，并支持HASPIN/H3T3ph的治疗性抑制作为CRC的潜在策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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