Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790M mutation resistant to gefitinib
© Xu et al.; licensee BioMed Central. 2015
Received: 30 September 2014
Accepted: 21 January 2015
Published: 5 February 2015
The T790M mutation of epithelial growth factor receptor (EGFR) is a major cause of the acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKIs) treatment for lung cancer patients. The Hippo pathway effector, TAZ, has emerged as a key player in organ growth and tumorigenesis, including lung cancer.
In this study, we have discovered high TAZ expression in non-small cell lung cancer (NSCLC) cells harboring dual mutation and TAZ depletion sensitized their response to EGFR-TKIs. Mechanistically, knockdown of TAZ in T790M-induced resistant cells leaded to reduced anchorage-independent growth in vitro, tumor formation and resistance to gefitinib in vivo, correlated with epithelial-mesenchymal transition (EMT) and suppressed migration and invasion. Furthermore, we confirmed CTGF and AXL, novel EMT markers and potential therapeutic targets for overcoming EGFR inhibitor resistance, as directly transcriptional targets of TAZ.
Taken together, this study suggests that expression of TAZ is an intrinsic mechanism of T790M-induced resistance in response to EGFR-TKIs. Combinational targeting on both EGFR and TAZ may enhance the efficacy of EGFR-TKIs in acquired resistance of NSCLC.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Despite the benefits shown with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with TKI-sensitive EGFR mutations such as delE746-A750 (exon 19) and L858R (exon 21), most patients ultimately relapse due to the development of drug resistance. A secondary point mutation in exon 20 of EGFR, which leads to substitution of methionine for threonine at position 790 (T790M), accounted for more than half of the cases with NSCLC who developed acquired resistance to the first-generation EGFR-TKIs (gefitinib and erlotinib) . The second-generation EGFR-TKIs, which form covalent, irreversible bonds with the target, are thought to be one strategy to overcome resistance. However, mounting studies have shown their limited activity in cells with T790M mutations  given acquiring ligand-independent oncogenic potential , more aggressive tumor phenotype and affecting other pathways . Therefore, to develop an effective therapy for patients harboring EGFR T790M is important to overcome the acquired resistance.
The transcriptional co-activator with PDZ-binding motif (TAZ), also known as WWTR1 for WW domain containing transcription regulator 1, was originally identified as a 14-3-3-binding proteins. Both TAZ and its paralog, Yes-associated protein (YAP), are key effectors of the Hippo pathway. Unlike YAP, knock-out of TAZ gene in mice does not overtly affect mouse development or fertility but selectively affects the construction and function of the lung and kidney . TAZ is known to bind to a variety of transcription factors to modulate mesenchymal stem cell differentiation , self-renewal of embryonic stem cell , crosstalk with other signaling pathways  and mechanotransduction .
Recent studies showed that TAZ promoted lung cancer/epithelial cell proliferation in vitro and tumor development in vivo. Higher TAZ expression was associated with poor differentiation, shorter survival and metastasis in lung cancer patients . Lately, microarray screening demonstrated that EGFR ligands (amphiregulin, epiregulin and neuregulin 1) were downstream targets of TAZ and EGFR signaling pathway was activated in NSCLC tissues with high TAZ expression [12, 13]. However, the roles of TAZ in therapeutic response of EGFR-TKI have not been explored. In this study, we provide evidence that TAZ-mediated tumorigenesis and progression correlated with gefitinib sensitivity in lung adenocarcinoma cells harboring EGFR T790M mutation.
High TAZ expression in NSCLC cells harboring EGFR T790M mutation
Effect of TAZ on sensitivity of NSCLC cells to gefitinib
TAZ is important for tumorigenesis and resistant to gefitinib of PC9/GR
TAZ mediates epithelial-mesenchymal transition (EMT) of gefitinib-resistant PC9/GR
Knockdown of TAZ in PC9/GR suppresses cell migration and invasion
Although tremendous progress has been made toward understanding the molecular mechanism underlying NSCLC development and treatment, the overall survival of lung cancer patients is still significantly hindered because of the evolution of drug-resistant tumors. T790M mutation-mediated gefitinib resistance accounts for 50% of TKI resistance in patients carrying an EGFR mutation. Accumulating evidence suggests that T790M-induced resistance is not only caused by lowering the affinity for gefitinib to nullify the hypersensitivity of activating EGFR mutations , but also attributed to the gain of transforming activity , potent proliferative and progressive advantage to cells expressing the T790M double mutants, with increasing ligand-independent receptor activation [3, 4].
Recently, TAZ and its paralogue YAP have been identified as major proteins mediating the effects of the novel Hippo tumor suppressor pathway. Several studies showed that TAZ amplification existed in lung cancer, driving the progression and metastasis of lung tumor-propagating cells  and significantly correlated with the prognosis of patients . In this report, we have for the first time identified TAZ as a novel gene responsible for sensitivity of gefitinib in NSCLC harboring T790M mutation. By overexpressing TAZ in gefitinib-sensitive PC9 cells, we found that enhanced levels of TAZ directly reduced sensitivity to growth inhibition induced by gefitinib, which abolished by the inhibition of Akt signaling. On the other hand, knockdown of endogenous TAZ in drug-resistant cells sensitized these cells to gefitinib. Therefore, targeting TAZ in TAZ-overexpressed, T790M-induced resistance might be a novel therapeutic strategy for sensitizing EGFR-TKI treatment.
Consistent with our finding, some proteins in the Hippo-LATS pathway have also been shown to mediate the drug sensitivity in human cancers. For example, Yang et al. have reported that TAZ and its downstream transcriptional targets cysteine-rich 61 (Cyr61) and CTGF mediated Taxol resistance in breast cancer cells . In a screen of shRNAs, LATS1, a negative regulator of TAZ, was identified as one of the genes causing paclitaxel resistance upon knockdown in A549 cells . Similarly, overexpression of YAP, the TAZ paralogue, has been found to involve in drug response of mammary , ovarian [19, 20], colon  and hepatocellular [22–25] cancers to multiple chemotherapeutic and targeted therapies. In addition, loss of other important tumor suppressor genes in the Hippo pathway such as Mst1, hEx and RASSF1A leads to drug resistance, whereas overexpression of CD44 or Itch, the negative regulators of the Hippo pathway, induces drug resistance . Together, these studies suggest that the emerging Hippo pathway may have significant roles in drug sensitivity of human cancers. Therefore, it will be very interesting to examine how TAZ is responsible for gefitinib sensitivity in NSCLC.
In current study, we provided evidence that endogenous TAZ contributed to the tumorigenicity of NSCLC cells harboring T790M mutant, as specific knockdown of TAZ leaded to reduced anchorage-independent growth in vitro and tumor formation in vivo. Preclinical and clinical data suggest that markers of EMT may be associated with limited responses to EGFR-TKI, whereas retention of an epithelial phenotype is associated with response even in patients without EGFR receptor mutations . Accumulating evidence suggests TAZ promotes EMT-mediated cancer progression [28, 29]. Consistent with these conclusion, our data showed knockdown of TAZ in PC9/GR was correlated with EMT as the transfectants demonstrated enhanced expression of epithelial marker (E-cadherin) but reduced mesenchymal markers (vimentin, CTGF and AXL). Furthermore, knockdown of TAZ in PC9/GR suppressed cell migration and invasion, which were considered functional hallmarks of EMT. These observations may partially explain the benefit of TAZ knockdown on EGFR-targeted therapy.
We further found stable TAZ knockdown dramatically reduced the expression of the classical Hippo target CTGF, a gene that regulated EMT-like transition. We showed that TAZ activated CTGF transcription by binding to and activating CTGF promoter. Consistent with our findings, previous studies showed that CTGF caused EMT-like cell fate mediated by TAZ-TEAD complex [16, 30, 31] and CTGF expression could confer resistance to chemotherapeutic agents through ERK1/2-dependent Bcl-xL/cIAP1 up-regulation in mastocarcinoma  and AMPK-dependent NF-κB pathway in osteosarcoma . Tyrosine kinase AXL, a novel EMT marker and potential therapeutic target for overcoming EGFR inhibitor resistance , was also confirmed as a transcriptional target of TAZ in current study. The synergistic interaction between EGFR and AXL signaling showed that AXL transactivation mediated by associated EGFR amplified the response of a subset of downstream elements, quantitatively shifting emphasis of the downstream network across multiple pathways . Moreover, this transactivation appeared to result from physical clustering interactions, which are quantitatively restricted to certain RTKs depending on a combination of intrinsic “affinity” and expression . Therefore, CTGF and AXL also contribute to the potential explanations for TAZ-related sensitivity of EGFR-TKI therapeutics.
In conclusion, we have provided convincing evidence that TAZ is a novel gene mediating tumorigenesis and EMT correlated with gefitinib sensitivity of lung adenocarcinoma cells harboring EGFR T790M mutation. Further confirmation of our findings using clinical patient samples will greatly facilitate our efforts in the sensitizing treatment of EGFR-TKI-resistant lung cancers in the future.
Human bronchial epithelial cell line 16HBE and lung adenocarcinoma cell line A549 were purchased from the Cell Resource Center (Shanghai Institutes for Biological Sciences, China). PC9, gefitinib-resistant PC9/GR, H1975 and cisplatin-resistant A549DDP cell lines were kindly provided by Prof. Hongbing Shen (Nanjing Medical University, Nanjing, China). All cells were grown in DMEM medium containing 10% FBS, 2mM L-glutamine and 100U/ml penicillin-streptomycin and incubated at 37°C with 5% CO2 in a humidified incubator. To maintain drug resistance, PC9/GR and H1975 cells were grown in DMEM containing 1 mg/ml gefitinib (Pure Chemistry Scientific Inc.) and then in drug free DMEM two days before experiments.
Plasmid and transfection
The target sequences that shTAZ1 and shTAZ2 aimed to were GCGATGAATCAGCCTCTGAAT and AGGTACTTCCTCAATCACA. PC9/GR and H1975 cells reaching 80% confluence were transfected with pGPU6-shTAZ in the presence of lipofectamine 2000 (Invitrogen). PC9/GR-shNC, PC9/GR-shTAZ1 and PC9/GR-shTAZ2 cells were generated from G418 selection as described previously. The plasmid of pEX2-TAZ was purchased from Origene (Rockville, MD, USA). pEX2-TAZ-S51A was constructed using the QuickChange Mutagenesis Kit (Stratagene) according to the manufacture's protocol. The DNA of CTGF [nucleotide (nt) position -250 to -1] and AXL (nt -1180 to -235) promoters were amplified by PCR from genomic DNA extracted from 16HBE cells and subsequently cloned into pGL3-basic luciferase reporter vector (Promega).
Total RNA was extracted from cells with TRIzol reagent (Invitrogen, San Diego, CA) according to the manufacturer’s instructions. cDNA was synthesized with the PrimeScript RT reagent kit (TaKaRa, Dalian, China). Quantitative RT-PCR was carried out with a SYBR Premix Ex Taq kit (TaKaRa) on a 7500 real time PCR system (ABI) as follows: 95°C for 30 s, 40 cycles at 95°C for 5 s, and 60°C for 30 s. The primers used were as follows: TAZ forward 5’-AGTACCCTGAGCCAGCAGAA-3’, reverse 5’-GATTCTCTGAAGCCGCAGTT-3’; CTGF forward 5’- CCCTCGCGGCTTACCGACTGG-3’, reverse 5’-CACAGGTCTTGGAACAGGCGC-3’; AXL forward 5’-TTTCCTGAGTGAAGCGGTCT-3’, reverse 5’-CATCTGAGTGGGCAGGTACA-3’; b-actin forward 5’-TGACGTGGACATCCGCAAAG-3’, reverse 5’-CTGGAAGGTGGACAGCGAGG-3’.
Immunofluorescence and western blot
Cells were fixed with 4% paraformaldehyde, permeabilized with 0.1% Triton X-100/PBS, blocked in 2% BSA/PBS and probed with primary antibody against TAZ (1:200, Cell Signaling Technology, Inc.), followed by incubation with fluorescein isothiocyanate-conjugated secondary antibodies (1:100, Sigma). Nuclei were stained with DAPI. All immunofluorescence was visualized by confocal microscopy (LSM 700), and images were processed using Volocity software (PerkinElmer Life Sciences). Images were quantitated using Image J software. For western blot analysis, 20 μg of whole-cell lysates and nuclear fractions were used. Nitrocellulose membranes were incubated with antibodies against TAZ, E-cadherin (1:200, Cell Signaling Technology, Inc.), Vimentin (1:200, abcam), CTGF (1:200, Proteintech Group, Inc.), AXL (1:200, abcam), tAKT, pAKT, tERK and pERK (1:100, Cell Signaling Technology, Inc.), GAPDH (1:5000, Santa Cruz Biotechnology) and histone H3 (1:2000, abcam) followed by horseradish peroxidase-linked secondary antibody. The target protein was visualized by chemiluminescence (Denville Scientific, Metuchen, NJ).
Cell viability assays
IC50 and inhibition rate of tumor growth was determined by the MTT (3-[4,5-dimethylthia-zol-2-yl]-2,5-diphenyltetrazolium bromide) assay (Sigma). Cancer cells were seeded into 96-well plates, and treated with gefitinib at different concentrations. After incubation, the media was replaced with 50 μL of MTT reagent (2 mg/mL) followed by further incubation in incubator for 2 h. Then, the media were removed and dimethylsulfoxide (DMSO) (150 μL) was added to each well. The absorbance at 560 nm was measured with a spectrophotometer.
Colony formation assay
Stable PC9/GR cells knocking down TAZ or the empty control were trypsinized and replated at 2 × 102 per well in 6-well plates. After 14 days in culture in DMEM supplemented with 10% FBS, colonies were fixed with 3.7% methanol and stained with Giemsa. Colonies containing at least 50 cells were scored.
Xenograft tumor model
Four- to 6-week-old female nude mice were inoculated subcutaneously in the left and right thigh with 5 × 106 PC9/GR-shNC and PC9/GR-shTAZ2 cells suspended in 100 μL of PBS to test tumorigenesis. Daily oral doses of gefitinib (75 mg/kg) in captisol solution were administered to tumor-bearing mice. Tumor size was measured twice a week to follow the drug response in animal model studies.
Triplicates of 5 × 104 16HBE and PC9/GR cells in a 12-well plate were transfected with CTGF-luc or AXL-luc alone or together with TAZ or TAZ-S51A, using Lipofectamine 2000 (Invitrogen). As an internal transfection control, 10 ng of Renilla luciferase vector was also cotransfected in each sample. Luciferase activity was measured 2 days after transfection, using the Dual Luciferase Reporter Assay System (Promega) and the Turner Biosystems 20/20 Luminometer.
Migration and invasion assays
Wound-healing assay was assessed by measuring the movement of monolayer cells into a acellular area created by a sterile plastic tip. The wound closure was photographed 24 h later by microscopy. Transwell migration and matrigel invasion assays were conducted using transwell plates with 8 μm pore size membranes (Corning Inc.). After incubation for 24 h, cells remaining in the upper side of the filter were removed with cotton swabs. The cells attached on the lower surface were fixed and stained. Cells were counted with five high power fields per membrane and results were presented as the mean number of cells migrated per field per membrane.
Statistical analysis was performed using the SPSS software package (SPSS Standard version 16.0, SPSS Inc). Data were shown as mean ± SEM. For in vitro and in vivo experiments, independent-samples t-test was used for assessing the significance of difference between the treatment and control groups. P value <0.05 was considered as statistically significant.
We wish to thank members of the Cheng laboratory for technical assistance. This work was a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, and also supported by grants from the International Science & Technology Cooperation Program of China (No. 2014DFA31940), and the National Natural Science Foundation of China (No. 81272602, 30971320, 81171962, 81261120386, 81302014).
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