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Objective <p>KIF15, a kinesin-12 family motor protein, has emerged as a recurrently upregulated factor in multiple human malignancies and has been implicated in diverse oncogenic processes. This review aims to provide a comprehensive synthesis of the molecular biology of KIF15, its oncogenic and non-oncogenic functions, the regulatory mechanisms governing its expression and activity, and its therapeutic potential across human disease contexts.</p> Methods <p>A comprehensive literature review was conducted using PubMed, Web of Science, and Scopus to identify studies addressing KIF15 structure, mitotic and non-mitotic functions, cancer-associated mechanisms, pharmacological targeting, and germline disease associations.</p> Results <p>KIF15 is frequently upregulated across multiple solid tumors—including lung, breast, prostate, pancreatic, gastric, colorectal, and hepatocellular cancers—and elevated expression is commonly associated with adverse clinical outcomes. Mechanistically, KIF15 activates mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK), phosphoinositide 3-kinase–protein kinase B (PI3K-AKT), and epidermal growth factor receptor (EGFR) signaling, androgen receptor (AR) and its splice variant androgen receptor splice variant 7 (AR-V7) to confer enzalutamide resistance, supports glycolytic reprogramming via phosphoglycerate kinase 1 (PGK1) deubiquitination, and maintains cancer stem cells (CSCs) phenotypes through reactive oxygen species (ROS) suppression. KIF15 additionally mediates adaptive resistance to kinesin-5 (Eg5, also known as KIF11), inhibitors via protein regulator of cytokinesis 1 (PRC1)-dependent antiparallel microtubule bundling. Beyond oncology, germline KIF15 variants have been associated with increased genetic susceptibility to idiopathic pulmonary fibrosis. Several KIF15-directed preclinical probes and proof-of-concept inhibitors have been reported, and dual Eg5/KIF15 inhibition has shown synergistic antitumor effects in experimental models.</p> Conclusions <p>KIF15 functions as a context-dependent regulator of mitotic adaptation and tumor progression, with reported roles in mitogenic signaling, metabolic reprogramming, and therapeutic resistance across multiple cancer types. Its chemical tractability and non-redundant role in drug-resistant spindle maintenance position it as a compelling candidate for combination anticancer strategies.</p>

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KIF15 (Kinesin-12): molecular biology, physiological functions, and roles in disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月10日

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  • Sumeng Xiang,
  • Yuxuan Li,
  • Haihui Zhuang,
  • Ying Lu

摘要

Objective

KIF15, a kinesin-12 family motor protein, has emerged as a recurrently upregulated factor in multiple human malignancies and has been implicated in diverse oncogenic processes. This review aims to provide a comprehensive synthesis of the molecular biology of KIF15, its oncogenic and non-oncogenic functions, the regulatory mechanisms governing its expression and activity, and its therapeutic potential across human disease contexts.

Methods

A comprehensive literature review was conducted using PubMed, Web of Science, and Scopus to identify studies addressing KIF15 structure, mitotic and non-mitotic functions, cancer-associated mechanisms, pharmacological targeting, and germline disease associations.

Results

KIF15 is frequently upregulated across multiple solid tumors—including lung, breast, prostate, pancreatic, gastric, colorectal, and hepatocellular cancers—and elevated expression is commonly associated with adverse clinical outcomes. Mechanistically, KIF15 activates mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK), phosphoinositide 3-kinase–protein kinase B (PI3K-AKT), and epidermal growth factor receptor (EGFR) signaling, androgen receptor (AR) and its splice variant androgen receptor splice variant 7 (AR-V7) to confer enzalutamide resistance, supports glycolytic reprogramming via phosphoglycerate kinase 1 (PGK1) deubiquitination, and maintains cancer stem cells (CSCs) phenotypes through reactive oxygen species (ROS) suppression. KIF15 additionally mediates adaptive resistance to kinesin-5 (Eg5, also known as KIF11), inhibitors via protein regulator of cytokinesis 1 (PRC1)-dependent antiparallel microtubule bundling. Beyond oncology, germline KIF15 variants have been associated with increased genetic susceptibility to idiopathic pulmonary fibrosis. Several KIF15-directed preclinical probes and proof-of-concept inhibitors have been reported, and dual Eg5/KIF15 inhibition has shown synergistic antitumor effects in experimental models.

Conclusions

KIF15 functions as a context-dependent regulator of mitotic adaptation and tumor progression, with reported roles in mitogenic signaling, metabolic reprogramming, and therapeutic resistance across multiple cancer types. Its chemical tractability and non-redundant role in drug-resistant spindle maintenance position it as a compelling candidate for combination anticancer strategies.