Abstract
BackgroundTelomere 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.MethodssiRNA 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.ResultsBy 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.ConclusionsThis 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.
Highlights
Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the “stemness” of multiple cancer cells
Knockdown of Transcriptional coactivator with PDZ-binding motif (TAZ) inhibits cell proliferation and causes cell senescence in triple negative breast cancers (TNBC) cells To know the potential roles of TAZ in the regulation of TNBC, we firstly examined the expressional levels of TAZ in both TNBC and non-TNBC
In accordance with the data from the above bioinformatic analyses, we found that both the mRNA and protein levels of TAZ are much higher in TNBC cell lines than that in non-TNBC (Fig. 1A, B)
Summary
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. We explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells. The cancers expressing none of these receptors are named triple negative breast cancer (TNBC). Previous studies reported that the expression of TAZ (Transcriptional coactivator with PDZ-binding motif ) is higher in TNBC than in the other types of breast cancers [2]. TAZ mainly acts as an effector of Hippo pathway to control organ size by regulating cell proliferation and apoptosis [3]
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