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.
Tong Wu, Yaguang Zhang, Sicheng Liu et al.· Molecular Cancer· 0 citations
Transfer RNA-derived small RNAs (tsRNAs) represent an emerging class of non-coding RNAs involved in gene expression and cellular homeostasis. Growing evidence suggests that tsRNAs contribute to tumor initiation and progression, in part by reshaping the tumor microenvironment (TME). This review systematically summarizes the biogenesis and molecular mechanisms of tsRNAs and discusses how they regulate key TME-associated processes, including immune cell function, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated intercellular communication. We further examine their clinical relevance, focusing on circulating biomarkers, therapeutic targeting and delivery strategies, as well as current limitations for translation. In the tumor microenvironment, tRNA-derived small RNAs regulate multiple interconnected processes, including immunosuppression, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated cell-cell communication, thereby contributing to tumor progression. In the tumor microenvironment, tRNA-derived small RNAs regulate multiple interconnected processes, including immunosuppression, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated cell-cell communication, thereby contributing to tumor progression.
Yaguang Zhang· Oncogene· 0 citations
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