通过抑制KIFC1破坏黑色素瘤细胞增殖

Melanoma remains among the ten most commonly diagnosed cancers in the United States, with persistently high mortality rates at advanced stages. In 2025, the American Cancer Society estimates 104,960 new cases and 8,430 deaths may be attributed to melanoma. The DREAMseq trial revealed objective response rates below 50% for both immunotherapies and targeted treatments, indicating that novel therapeutic targets are needed to improve outcomes. Previous work has initiated interest in KIFC1, a microtubule-based motor protein, in melanoma due to elevated expression levels and poorer survival outcomes in patients. In cells with amplified centrosomes, KIFC1 may aid in cancer development and progression, likely through clustering of aberrant centrosomes. The resulting pseudo-bipolar orientation can enable daughter cell survival but may lead to aneuploidy and chromosomal instability. Prior experiments revealed significant decreases in melanoma cell growth using the small molecule inhibitor AZ82. To further identify the mechanisms responsible for the KIFC1 inhibition phenotype, A375 human melanoma cells were treated with AZ82, followed by RNASeq. The treatment induced a differential expression of 1035 and 587 genes upregulated and downregulated respectively compared to DMSO control with |fold change| ≥2 and adjusted p-value ≤0.05. Hallmark gene set analysis revealed significant increases of genes related to Hypoxia, Cholesterol Homeostasis, TNF-alpha Signaling, and Myogenesis. The data also supported a decrease in E2F Targets, G2M Checkpoint and MYC Targets V1 and V2 in AZ82 treated cells. This data suggests the KIFC1 inhibition phenotype is modulated by interactions beyond its role in centrosome clustering. To further assess longer-term knockdown effects, stable shRNA mediated knockdown cell lines were generated. A375 and Hs294T sh-KIFC1 cell lines grew significantly slower than sh-NS control. Growth reductions were further supported by orthogonal clonogenic survival indicating sustained genetic inhibition of KIFC1 reduces melanoma cell growth. Together, our data support the hypothesis that KIFC1 exhibits a pro-proliferative role in melanoma. These findings and future in vivo experiments will establish the therapeutic significance of KIFC1 inhibition in melanoma.