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 4

KIF20A depletion decreases BCSC self-renewal and TNBC tumorigenesis in vivo.

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KIF20A depletion decreases BCSC self-renewal and TNBC tumorigenesis in v...
(A and B) Limiting dilution tumor-initiating assay of MDA-MB-231 cells infected with lentivirus encoding control or KIF20A sgRNA #1 or #3. n = 5 mice for each group. (C–E) Limiting dilution tumor-initiating assay (C), harvested tumor images (D), and tumor volume at the end point (E) in HCC1806 cells infected with lentivirus encoding control or KIF20A sgRNA #1. n = 6 mice for each group. (F–H) Tumor growth (F), tumor weight (G), and tumor images after sacrifice (H) of MDA-MB-231 stable cells infected with lentivirus encoding control or KIF20A sgRNA #1 injected into mammary glands of NSG mice. (I) Limiting dilution tumor-initiating assay of MDA-MB-231 cells expressing control or KIF20A sgRNA and GFP or sgRNA-resistant KIF20A mutant as indicated. (J–L) Tumor growth (J), tumor weight (K), and tumor images after sacrifice (L) of MDA-MB-231 stable cells expressing control or KIF20A sgRNA and GFP or sgRNA-resistant KIF20A mutant as indicated in NSG mice. Each data point represents a biological replicate. Data represent mean ± SEM. Statistical analyses were conducted by χ2 test (A–C and I), 2-tailed Student’s t test (E and G), 2-way ANOVA (F and J), or 1-way ANOVA with Tukey’s test (K). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bars: 1 cm.