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

• Published in: Oncogene Vol. 40; no. 12; pp. 2323 - 2334
• Main Authors: Ge, Li-Ping, Jin, Xi, Yang, Yun-Song, Liu, Xi-Yu, Shao, Zhi-Ming, Di, Gen-Hong, Jiang, Yi-Zhou
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.03.2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 13/89; 14/19; 38/77; 59/5; 631/67/1059/602; 631/67/1347; 631/67/322; 64/60; 82/58; 82/80; Acetylation - drug effects; Animals; Apoptosis; Breast cancer; Cell Biology; Cell culture; Cell Movement - drug effects; Cell Proliferation - drug effects; Deacetylation; Disease Models, Animal; Exome Sequencing; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Heterografts; Histone deacetylase; Histone Deacetylase 6 - genetics; Histone Deacetylase Inhibitors - pharmacology; Human Genetics; Humans; Hydroxamic Acids - pharmacology; Internal Medicine; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Microtubule Proteins - genetics; Microtubule-associated proteins; Microtubules; Neoplasm Metastasis; Oncology; Organoids; Physiological aspects; Pseudogenes; Pyrimidines - pharmacology; Sequence Analysis, RNA; Transcriptomes; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tubulin; Tubulin - genetics; Xenografts; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01655-2

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.