TAZ maintains telomere length in TNBC cells by mediating Rad51C expression.
TAZ maintains telomere length in TNBC cells by mediating Rad51C expression.
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TAZ 通过介导 Rad51C 表达维持 TNBC 细胞中的端粒长度
DOI：
10.1186/s13058-021-01466-z
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发表时间：
2021-09-06
期刊：
影响因子：
--
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Yang L;Wang B;Jiao X;Zhou C;Chen S;Gao X;Sun W;Song S;Li J;Liu J;Wang Y;Liu P
端粒维持对于癌细胞的无限增殖至关重要，并且对于多种癌细胞的“干性”至关重要。TAZ在三阴性乳腺癌（TNBC）中比在其他类型的乳腺癌中更广泛地表达，并促进癌细胞的增殖、转化和EMT。据报道，TAZ使乳腺癌细胞具有癌症干细胞特征。然而，TAZ是否调节端粒仍不清楚。在这项研究中，我们探讨了TAZ在TNBC细胞中调节端粒维持的作用。siRNA和shRNA用于产生TAZ耗尽的TNBC细胞系。采用qPCR和Southern末端限制性片段分析技术检测端粒长度。采用免疫共沉淀、免疫印迹、免疫荧光、荧光素酶报告基因分析和Chromatin-IP等方法研究其作用机制。通过敲低TNBC细胞中TAZ的表达，我们首次发现TAZ对于TNBC细胞中端粒的维持是必不可少的。此外，TAZ的缺失导致TNBC细胞的衰老表型。在TAZ敲除细胞的晚期传代中观察到的极度缩短的端粒与hTERT表达升高、shelterin蛋白减少和激活的DNA损伤反应途径相关。我们的数据还表明，TAZ的缺失导致TERRA的过表达，TERRA是一组含有端粒重复序列的RNA，调节端粒长度和完整性。此外，我们发现TAZ可能通过促进Rad 51 C的表达来维持TNBC细胞的端粒长度，Rad 51 C是促进端粒复制的同源重组途径的关键元件。这项研究支持TAZ是TNBC中的致癌因子的观点，并进一步揭示了TAZ用于调节TNBC的新的端粒相关通路。在线版本包含补充材料，可通过10.1186/s13058-021-01466-z获得。
Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the “stemness” of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells. siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism. By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat‐containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication. This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC. The online version contains supplementary material available at 10.1186/s13058-021-01466-z.
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