2. Academic Validation
  3. Tektin4 loss promotes triple-negative breast cancer metastasis through HDAC6-mediated tubulin deacetylation and increases sensitivity to HDAC6 inhibitor

Tektin4 loss promotes triple-negative breast cancer metastasis through HDAC6-mediated tubulin deacetylation and increases sensitivity to HDAC6 inhibitor

  • Oncogene. 2021 Mar;40(12):2323-2334. doi: 10.1038/s41388-021-01655-2.
Li-Ping Ge  # 1 2 3 4,  Xi Jin  # 1 3 4,  Yun-Song Yang 1 3 4,  Xi-Yu Liu 1 3 4,  Zhi-Ming Shao 1 2 3 4 5 6,  Gen-Hong Di 7 8 9 10 11,  Yi-Zhou Jiang 12 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China.
  • 2 Human Phenome Institute, Fudan University, Shanghai, PR China.
  • 3 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, PR China.
  • 4 Key Laboratory of Breast Cancer in Shanghai, Shanghai, PR China.
  • 5 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China.
  • 6 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, PR China.
  • 7 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China. genhongdi@163.com.
  • 8 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, PR China. genhongdi@163.com.
  • 9 Key Laboratory of Breast Cancer in Shanghai, Shanghai, PR China. genhongdi@163.com.
  • 10 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China. genhongdi@163.com.
  • 11 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, PR China. genhongdi@163.com.
  • 12 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China. yizhoujiang@fudan.edu.cn.
  • 13 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, PR China. yizhoujiang@fudan.edu.cn.
  • 14 Key Laboratory of Breast Cancer in Shanghai, Shanghai, PR China. yizhoujiang@fudan.edu.cn.
  • 15 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China. yizhoujiang@fudan.edu.cn.
  • 16 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, PR China. yizhoujiang@fudan.edu.cn.
  • # Contributed equally.
PMID: 33654196 DOI: 10.1038/s41388-021-01655-2
Abstract

Progression of triple-negative breast Cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast Cancer metastasis, we performed RNA Sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived Organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.

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