Targeting kinesin family member 20A sensitizes stem-like triple-negative breast cancer cells to standard chemotherapy
Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang
Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang
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Research Article Cell biology Oncology

Targeting kinesin family member 20A sensitizes stem-like triple-negative breast cancer cells to standard chemotherapy

Abstract

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. Mechanistically, KIF20A supports BCSC stemness through modulation of mitochondrial oxidative phosphorylation, which is repressed by SMARCA4, a component of the SWI/SNF chromatin remodeling complex. Therapeutically, KIF20A inhibition sensitizes TNBC xenografts to standard-of-care chemotherapy. Our study highlights the importance of targeting KIF20A to exploit BCSC vulnerabilities in TNBC.

Authors

Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

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Figure 6

KIF20A affects the expression of mitochondrial OXPHOS genes.

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KIF20A affects the expression of mitochondrial OXPHOS genes. (A–D) Gene ...
(A–D) Gene set enrichment analysis (GSEA) showing the top hallmark pathways enriched in the control sgRNA compared with KIF20A sg1 (A) or KIF20A overexpression compared with the EV control (C) in MDA-MB-231 cells. GSEA enrichment plots of the OXPHOS pathways from KIF20A knockdown (B) and KIF20A overexpression (D) are shown. (E) Heatmap of genes related to mitochondrial complex I–V in control or KIF20A-depleted and -overexpressing MDA-MB-231 cells from the RNA-Seq data. n = 3. (F) Venn diagram of significant genes associated with mitochondrial complexes identified from the KIF20A-depleted and -overexpressing RNA-Seq experiments. (G) Representative genes selected for functional validation from each mitochondrial complex. (H) RT-qPCR analysis of selected OXPHOS genes in KIF20A-depleted HCC1806 cells. n = 3. (I) RT-qPCR analysis of OXPHOS genes in HCC1806 cells with KIF20A overexpression. n = 3. (J) RT-qPCR analysis of OXPHOS genes in KIF20A cells rescued by sgRNA-resistant KIF20A mutant in MDA-MB-231 cells. n = 3. (K) RT-qPCR analysis of OXPHOS genes in HCC1806 cells treated with paprotrain. n = 6. Each data point represents a biological replicate. Data represent mean ± SEM. Statistical analyses were conducted by 1-way ANOVA with Dunnett’s test (H), 2-tailed Student’s t test (I and K), or 1-way ANOVA with Tukey’s test (J). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.