Abstract
Antitubulin drugs are commonly used for the treatment of numerous cancers. However, either the intrinsic or acquired resistances of patients to these drugs result in the failure of the treatment and high mortality of cancers. Therefore, identifying genes or signalling pathways involved in antitubulin drug resistances is critical for future successful treatment of cancers.TAZ (Transcriptional coactivator with PDZ-binding motif), which is a core component of the Hippo pathway, is overexpressed in various cancers. We have recently shown that high levels of TAZ in cancer cells result in Taxol resistance through up-regulation of downstream targets Cyr61 and CTGF. However, how TAZ is regulated in response to Taxol is largely unknown. In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. Phosphorylation-mimicking TAZ mutant was unstable, and therefore abolished TAZ-induced antitubulin drug resistances. This study provides first evidence that Cdk1 is a novel kinase phosphorylating and regulating TAZ stability and suggests that Cdk1-TAZ signalling is a critical regulator of antitubulin drug response in cancer cells and may be a potential target for the treatment of antitubulin-drug resistant cancer patients.
Highlights
Antitubulin drugs including paclitaxel (Taxol) and vinblastine are the chemotherapeutic drugs widely used for clinical cancer treatment of several types of cancers such as breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer, etc [1,2,3,4]
These findings strongly suggest that degradation of TAZ is correlated with the sensitivity of cancer cells to antitubulin drug Taxol
We and others have recently shown that dysregulation of the core Hippo pathway components such as LATS, YAP, and TAZ results in resistances of tumors to various chemotherapeutic drugs such as Taxol, Doxorubicin, erlotinib, RAF/MEK inhibitors, etc [19, 34]
Summary
Antitubulin drugs including paclitaxel (Taxol) and vinblastine are the chemotherapeutic drugs widely used for clinical cancer treatment of several types of cancers such as breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer, etc [1,2,3,4]. TAZ (Transcriptional co-activator with PDZ binding motif), named as WWTR1 (WW domain containing transcription regulator 1), is one of the core components (MST-LATS-YAP/TAZ) in the Hippo pathway that plays important roles in tumorigenesis, organ size control, stem cell differentiation and renewal, etc [7,8,9,10,11] It is well-known that TAZ can be phosphorylated by LATS (Large tumor suppressor) through four serine (S) sites, which can cause TAZ either bind to 14–3–3 protein and is anchored in cytoplasm or be degraded through ubiquitinproteasome-system (UPS) by interacting with E3 ubiquitin ligase β-TRCP [12, 13]. This study discovers an essential role of Cdk1-TAZ signalling in determining the tumor cell sensitivity to antitubulin drugs and suggests a novel signalling target for the treatment of antitubulin drug-resistant cancers
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