Drug resistance is a major challenge in cancer treatment. Emerging evidence indicates that deregulation of YAP/TAZ signaling may be a major mechanism of intrinsic and acquired resistance to various targeted and chemotherapies. Moreover, YAP/TAZ-mediated expression of PD-L1 and multiple cytokines is pivotal for tumor immune evasion. While direct inhibitors of YAP/TAZ are still under development, FDA-approved drugs that indirectly block YAP/TAZ activation or critical downstream targets of YAP/TAZ have shown promise in the clinic in reducing therapy resistance. Finally, BET inhibitors, which reportedly block YAP/TAZ-mediated transcription, present another potential venue to overcome YAP/TAZ-induced drug resistance.

YAP/TAZ Signaling and Resistance to Cancer Therapy.

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

YAP/TAZ Activation as a Target for Treating Metastatic Cancer.

The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, here we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented. Using ChIP-PCR, we validate TEAD1 trans occupancy at accessibility sites within AQP4, EGFR, and CDH4. To further characterize TEAD’s functional role in GBM, we knockout TEAD1 or TEAD4 in patient-derived GBM lines using CRISPR-Cas9. TEAD1 ablation robustly diminishes migration, both in vitro and in vivo, and alters migratory and EMT transcriptome signatures with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression, and both TEAD1 and AQP4 overexpression rescue migratory deficits in TEAD1-knockout cells, implicating a direct regulatory role for TEAD1–AQP4 in GBM migration.

Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma

EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1 and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 11 were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole 1, 2, 7-9, and 15, pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine 3-6, pyrazolo[3,4-d]pyrimidine 12 and 13, and pyrazolo[3,4-c]pyrazole 14 derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds 1, 2, 4, 8, 11, 12, and 15 showed nearly 10 fold higher activity than erlotinib (10.6 μM) with IC50 ranging from 0.31 to 0.71 μM. In vitro EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound 3 as the most potent EGFR inhibitor (IC50 = 0.06 μM) and compound 9 as the most potent VEGFR-2 inhibitor (IC50 = 0.22 μM). Moreover, compounds 9 and 12 revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.

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Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors.

Myricetin is a naturally occurring flavonoid with protective effects against a variety of cancers. However, the molecular mechanism of myricetin against hepatocellular carcinoma (HCC) has still not been fully elucidated. Previous studies have indicated that YAP is essential for cancer initiation and progression. However, whether YAP contributes to the anti-cancer effects of myricetin remains unclear. Herein, we aimed to investigate the effect of myricetin on HCC, and identify the underlying mechanisms. We report that myricetin induced apoptosis and proliferation inhibition in HepG2 and Huh-7 cells. Myricetin inhibited expression of YAP by promoting its phosphorylation and subsequent degradation. Myricetin inhibited YAP expression by stimulating kinase activation of LATS1/2. Knockdown expression of LATS1/2 by shRNA attenuated myricetin-induced phosphorylation and degradation of YAP. Furthermore, myricetin sensitized HCC cells to cisplatin treatment through inhibiting YAP and its target genes, both in vitro and in vivo. The identification of the LATS1/2-YAP pathway as a target of myricetin may help with the design of novel strategies for human HCC prevention and therapy.

Myricetin Suppresses the Propagation of Hepatocellular Carcinoma via Down-Regulating Expression of YAP.

125I suppressed the Warburg effect viaregulating miR-338/PFKL axis in hepatocellular carcinoma

Triple-negative breast cancer (TNBC) constitutes ~10-15% of breast cancer patients and represents an aggressive subtype with poor overall prognosis. TNBC is an important clinical challenge because it does not respond well to endocrine therapy and have a higher rate of early recurrence and distant metastasis following chemotherapy. Although it has been reported that the epidermal growth factor receptor (EGFR) was overexpressed in ~80% of TNBC, anti-EGFR therapy showed limited clinical benefit according to phase II studies. In this study, we first observed that knockdown of the transcriptional coactivator with PDZ-binding domain (TAZ) gene can regulate the sensitivity of TNBC cell lines to EGFR inhibitors (EGFRI) in a cell context-depended manner. Furthermore, in certain breast cancer cell lines the YES-associated protein, paralog of TAZ (YAP) expression can be upregulated by TAZ inhibition which leads to EGFRI resistance. These results suggest a specific inhibitor to TAZ/YAP combined with anti-EGFR therapy may prove effective and provide a reason why targeting EGFR showed limited clinical benefit in TNBC treatment.

/pdf/knockdown-of-taz-modifies-triple-negative-breast-cancer-cell-4irk8bcw2f.pdf

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

Liver cancer is the third most common cause of cancer related death worldwide. Apatinib showed satisfactory efficacy in various types of cancers, including breast cancer, malignant fibrous histiocytoma and liver cancer. However, how did Apatinib function in liver cancer is largely unknown. mRNA levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) as well as protein levels of VEGF and p-VEGFR2 were obviously higher in liver cancer cell line SMCC7721 than in normal liver cell LO2. Apatinib significantly inhibited the mRNA levels of VEGF and VEGFR2 as well as protein levels of VEGF and p-VEGFR2 compared with those in control group. At 12, 24 and 48 h after corresponding treatments, compared with the control group, Apatinib significantly lowered the cell viability of SMCC7721 cells, while transfection of si-signal transducer and activator of transcription 3 (siSTAT3) further augmented the effects of Apatinib. At 48 h after treatment, compared with the control group, Apatinib significantly upregulated the cell apoptosis rate of SMCC7721 cells, which was further induced by the transfection of siSTAT3. Compared with control group, Apatinib significantly induced BAX/Bcl-2 ratio elevation, reduced p-STAT3 and p-VEGFR2 expression, which were significantly augmented by the treatment of siSTAT3. In conclusion, Apatinib inhibited the cell proliferation and promoted the cell apoptosis of liver cancer by inhibiting the activation of VEGFR2/STAT3.

Apatinib regulates the cell proliferation and apoptosis of liver cancer by regulation of VEGFR2/STAT3 signaling

Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide, however, the prognosis for HCC remains unsatisfactory. This study aimed to explore the role of miR-339-5p in HCC. Methods We first used quantitative real-time PCR to examine the level of miR-339-5p in HCC tissues. Then we further adopted Western blotting assay, CCK8, cell invasion assays, apoptosis detection assay, and luciferase assay to analyze how it mediate the development of HCC. Results We found that miR-339 is significantly decreased in primary HCC tissues. Overexpression of miR-339 in HCC cells remarkably suppressed proliferation and invasion and induced apoptosis. However, silencing miR-339 in HCC cells promoted proliferation and invasion, and reduced apoptosis. Moreover, we demonstrated that ZNF689 is a target of miR-339 and there is a negative correlation between miR-339 and ZNF689 expression in the HCC tissues. Overexpression of ZNF689 in miR-339-overexpressing HCC cells partially antagonized the inhibitory effects of miR-339. Conclusion Our study revealed that miR-339 inhibits HCC growth through targeting oncoprotein ZNF689 and restoration of miR-339 might be feasible therapeutic strategy for HCC treatment.

/pdf/microrna-339-inhibits-human-hepatocellular-carcinoma-2dofset3ss.pdf

MicroRNA-339 inhibits human hepatocellular carcinoma proliferation and invasion via targeting ZNF689.

Purpose: To evaluate the advantages and primary technical efficacy of an electromagnetic (EM) navigation system for computed tomography (CT)-guided thermal ablation of liver tumors.Material and met...

Jiaping Zheng

Papers

125I suppressed the Warburg effect viaregulating miR-338/PFKL axis in hepatocellular carcinoma

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

Apatinib regulates the cell proliferation and apoptosis of liver cancer by regulation of VEGFR2/STAT3 signaling

MicroRNA-339 inhibits human hepatocellular carcinoma proliferation and invasion via targeting ZNF689.

Electromagnetic navigation to assist with computed tomography-guided thermal ablation of liver tumors.