Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

Guo, Lili; Zheng, Jiaping; Zhang, Jing; Wang, Haohao; Shao, Guoliang

doi:10.3892/or.2016.4875

Cited by 24 publications

(12 citation statements)

References 22 publications

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“…Strikingly, we recently showed that inhibition/depletion of PYK2 also facilitates the degradation of HER3, and that inhibition of PYK2 not only sensitized basal-like TNBC to EGFR antagonists but could also circumvent HER3-associated drug resistance 28 . Consistent with our findings, a previous report showed that TAZ KD sensitized TNBC cells to EGFR antagonists 38 . Hence, it could be that PYK2 inhibition sensitized basal-like TNBC to EGFR antagonists, at least in part, by destabilizing TAZ.…”

Section: Discussionsupporting

confidence: 93%

PYK2 negatively regulates the Hippo pathway in TNBC by stabilizing TAZ protein

et al. 2018

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The tumor suppressor Hippo pathway negatively regulates the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to inhibit cell growth and control organ size, whereas activation of YAP and TAZ is implicated in tumorigenesis and cancer metastasis. Here, we report that the nonreceptor tyrosine kinase PYK2 positively regulates TAZ and YAP transcriptional activity in triple-negative breast cancer (TNBC). We found that inhibition of PYK2 expression or its kinase activity substantially affects the steady-state level of TAZ and markedly facilitates its proteasomal degradation. This effect was specific to PYK2 inhibition and was not obtained by inhibition of FAK. Destabilization of TAZ was associated with profound effect of PYK2 inhibition on cell growth at low-density concomitant with reduced expression of TAZ-target genes and induction of cell apoptosis. We further show that PYK2 enhances the tyrosine phosphorylation of both TAZ and LATS1/2 and concomitantly TAZ stability, and that PYK2 protein level correlates with the level of TAZ protein in primary breast tumors. Together these observations suggest that PYK2 is an important regulator of the Hippo pathway, and its tyrosine kinase activity has a striking effect on TAZ stabilization and activation in TNBC.

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Section: Discussionsupporting

confidence: 93%

PYK2 negatively regulates the Hippo pathway in TNBC by stabilizing TAZ protein

et al. 2018

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“…Our results also indicated that downregulation of TAZ could be a useful strategy for restoring sensitivity to cisplatin. Indeed, one study has shown that knockdown of TAZ modified breast cancer cell sensitivity to EGFR inhibitors (50). In line with this, we found that depletion of TAZ sensitized CR cells to cisplatin treatment.…”

Section: Discussionsupporting

confidence: 88%

TAZ overexpression is associated with epithelial-mesenchymal transition in cisplatin-resistant gastric cancer cells

Chen

et al. 2017

International Journal of Oncology

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Gastric cancer is one of the common malignant diseases. The poor treatment outcome is mainly due to chemotherapeutic resistance. Therefore, it is important to determine the molecular mechanism of drug resistance in gastric cancer. To explore the mechanisms of cisplatin resistance in gastric cancer cells, several approaches were performed including MTT assay, real-time RT-PCR, western blot analysis, migration and invasion assays, wound healing assay, and transfection. We found that cisplatin-resistant (CR) gastric cancer cells acquired epithelial-mesenchymal transition (EMT) phenotype. The CR cells with EMT features obtained higher migratory and invasive activities. Moreover, we observed that TAZ was highly expressed in CR cells. Consistently, depletion of TAZ caused partial reversal of EMT to MET in CR cells. Our results suggest that TAZ plays a pivotal role in CR-induced EMT. Targeting TAZ could be a potential therapeutic strategy for gastric cancer.

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“…Then, YAP translocates to the nucleus, where it forms a complex with TEAD and regulates the expression of multiple genes [6][7][8]. Numerous studies have shown the up-regulation of YAP in the tumors, such as liver cancer, breast cancer and so on [9][10][11][12]. It has been reported that the expression of TAZ is positively regulated by EBV-LMP1 and contributes to cell proliferation and epithelial-mesenchymal transition in NPC [13].…”

Section: Introductionmentioning

confidence: 99%