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
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Tektin4 缺失通过 HDAC6 介导的微管蛋白脱乙酰化促进三阴性乳腺癌转移，并增加对 HDAC6 抑制剂的敏感性
DOI：
10.1038/s41388-021-01655-2
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发表时间：
2021-03-02
期刊：
影响因子：
8
通讯作者：
Jiang, Yi-Zhou
中科院分区：
文献类型：
--
作者：
Ge, Li-Ping;Jin, Xi;Jiang, Yi-Zhou
三阴性乳腺癌（TNBC）的进展构成了一个尚未解决的主要临床挑战，缺乏有效的靶向治疗。由于微管动力学在乳腺癌转移中起着关键作用，我们对来自TNBC患者的245个样本进行了RNA测序，以表征微管相关蛋白（MAP）的景观。在这里，我们的转录组分析显示，一种MAP，tektin 4的低表达表明患者预后不良。Tektin 4丢失导致TNBC迁移、侵袭和转移的显著增加以及微管稳定性的降低。从机制上讲，我们发现了一种新的微管相关复合物，含有tektin 4和组蛋白脱乙酰酶6（HDAC 6）。Tektin 4的缺失增加了HDAC 6和α-微管蛋白之间的相互作用，从而通过HDAC 6介导的微管蛋白脱乙酰化降低了微管稳定性。值得注意的是，我们发现tektin 4损失使TNBC细胞、异种移植模型和患者来源的类器官模型对HDAC 6选择性抑制剂ACY 1215敏感。此外，tektin 4表达水平与临床样品中微管稳定性水平呈正相关。总之，我们的研究结果揭示了tektin 4的转移抑制功能，并支持HDAC 6抑制作为tektin 4缺陷型TNBC患者的新治疗策略的临床开发。
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.