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 10

KIF20A controls OXPHOS genes and BCSCs through SMARCA4.

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KIF20A controls OXPHOS genes and BCSCs through SMARCA4. (A–C) Immunoblot...
(A–C) Immunoblot analysis of SMARCA4 protein (A), RT-qPCR analysis of OXPHOS genes (n = 3) (B), and measurement of OCR (C) in MDA-MB-231 cells transduced with indicated control or SMARCA4 shRNAs. (D–F) Immunoblot analysis of KIF20A and SMARCA4 (D) and RT-qPCR analysis of OXPHOS genes in MDA-MB-231 (E) and HCC1806 (F) cells transduced with control or KIF20A sgRNA and control or SMARCA4 shRNA as indicated. n = 3. (G and H) Measurement of OCR (n = 5) (G) and mammosphere formation assay and corresponding quantifications (n = 3) (H) in MDA-MB-231 cells transduced with control or KIF20A sgRNA and control or SMARCA4 shRNA as indicated. Scale bar: 1 mm. (I) ChIP-PCR analysis of KIF20A and SMARCA4 binding at the promoters of OXPHOS genes in MDA-MB-231 cells. n = 3. (J) ChIP-PCR analysis of SMARCA4 binding at the promoters of OXPHOS genes in MDA-MB-231 cells transduced with control or KIF20A sgRNAs. n = 3. (K) Schematic model of the mechanism proposed for this study. Each data point represents a biological replicate. Data represent mean ± SEM. Statistical analyses were conducted by 1-way ANOVA with Dunnett’s test (B, I, and J) or with Tukey’s test (E, F, and H). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.