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

Oncogene volume 40, pages 2323–2334 (2021)Cite this article

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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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Fig. 1: Transcriptome analyses of MAPs identified tektin4 as a potential metastasis suppressor in TNBC.
Fig. 2: Tektin4 loss promotes TNBC cell invasion and tumor metastasis.
Fig. 3: Tektin4 interacts with the HDAC6 protein.
Fig. 4: Tektin4 loss decreases microtubule stability via HDAC6-mediated deacetylation.
Fig. 5: Tektin4 loss sensitizes TNBC to HDAC6 inhibition with ACY1215.
Fig. 6: Correlation between tektin4 and acetylated α-tubulin in TNBC samples.

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Data availability

FUSCC TNBC sequence data have been deposited in the NCBI Gene Expression Omnibus (OncoScan array; GEO: GSE118527) and Sequence Read Archive (whole exome sequencing and RNA-seq; SRP157974) [48].

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Acknowledgements

We would like to thank all the patients at Fudan University Shanghai Cancer Center for their support and commitment to tissue collection and banking. This work was supported by grants from the National Natural Science Foundation of China (81874112, 91959207, 81922048, 81902684, 81874113), the Program of Shanghai Academic/Technology Research Leader (20XD1421100), the Fok Ying-Tong Education Foundation for College Young Teachers (171034), the Shanghai Sailing Program (19YF1409000), the Innovation Team of Ministry of Education (IRT1223) and the Shanghai Key Laboratory of Breast Cancer (12DZ2260100).

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  1. These authors contributed equally: Li-Ping Ge, Xi Jin

Authors and Affiliations

  1. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China

    Li-Ping Ge, Xi Jin, Yun-Song Yang, Xi-Yu Liu, Zhi-Ming Shao, Gen-Hong Di & Yi-Zhou Jiang

  2. Human Phenome Institute, Fudan University, Shanghai, PR China

    Li-Ping Ge & Zhi-Ming Shao

  3. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, PR China

    Li-Ping Ge, Xi Jin, Yun-Song Yang, Xi-Yu Liu, Zhi-Ming Shao, Gen-Hong Di & Yi-Zhou Jiang

  4. Key Laboratory of Breast Cancer in Shanghai, Shanghai, PR China

    Li-Ping Ge, Xi Jin, Yun-Song Yang, Xi-Yu Liu, Zhi-Ming Shao, Gen-Hong Di & Yi-Zhou Jiang

  5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China

    Zhi-Ming Shao, Gen-Hong Di & Yi-Zhou Jiang

  6. Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, PR China

    Zhi-Ming Shao, Gen-Hong Di & Yi-Zhou Jiang

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Contributions

LPG and XJ contributed equally to this work. YZJ and GHD were the principal investigators who conceived the study and secured funding. YZJ, GHD, and XJ coordinated and oversaw the study. LPG and XJ performed the experiments, analyzed the data, and wrote the manuscript. XYL and YSY performed the organoid experiments. All authors have read and approved the manuscript.

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Correspondence to Gen-Hong Di or Yi-Zhou Jiang.

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All mouse experiment procedures were reviewed and approved by the Experimental Animal Ethics Committee of Fudan University.

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Ge, LP., Jin, X., Yang, YS. et al. Tektin4 loss promotes triple-negative breast cancer metastasis through HDAC6-mediated tubulin deacetylation and increases sensitivity to HDAC6 inhibitor. Oncogene 40, 2323–2334 (2021). https://doi.org/10.1038/s41388-021-01655-2

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