YAP and TAZ: Monocorial and bicorial transcriptional co-activators in human cancers

Sardo, Federica Lo; Canu, Valeria; Maugeri‐Saccà, Marcello; Strano, Sabrina; Blandino, Giovanni

doi:10.1016/j.bbcan.2022.188756

Cited by 16 publications

(26 citation statements)

References 148 publications

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“…YAP, also known as YAP1, is a transcription regulator of the Hippo pathway and hasimportant biological properties in cell proliferation, mature cells dedifferentiation, tumorigenesis and reprogramming of cellular metabolism [15]. When the pathway is activated, YAP accumulates in the nucleus and the transcriptional co-activators of YAP and TAZ are recruited to target site by TEAD.…”

Section: Introductionmentioning

confidence: 99%

A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming

et al. 2022

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Background Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers. Methods Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer. Results WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis. Conclusion The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.

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Section: Introductionmentioning

confidence: 99%

A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming

et al. 2022

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“…2G, H ). TAZ activity is primarily regulated by protein abundance while YAP activity is by the nuclear-cytoplasmic shuttle [ 10 ]. So we analyzed the nuclear and cytoplasmic localization of YAP in the same experimental conditions, and results revealed that with MPA treatment in dose and time dependent ways, YAP might play a role in promoting progestin resistance mainly in the nucleus (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…There are many studies indicating that YAP and TAZ as a whole are involved in the drug resistance process and targeting YAP and TAZ could overcome drug resistance of tumors [ 10 , 24 , 25 ]. In order to verify how YAP/TAZ function in progestin resistance of EC, we performed a series of experiments in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…YAP/TAZ are transcriptional coactivators and commonly known as the downstream effectors of Hippo pathway which was originally discovered in Drosophila [ 9 ]. In a variety of tumors such as breast, lung, colorectal, and intestinal cancers, YAP and TAZ play distinct and overlapping functions as they are regulated by multiple factors [ 10 ]. In breast cancer, for example, both YAP and TAZ are highly expressed in a variety of breast tumor subtypes; however, YAP can function as oncogene or proto-oncogene due to the different breast cancer subtypes and the influence of environmental and experimental conditions.…”

Section: Introductionmentioning

confidence: 99%

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Verteporfin reverses progestin resistance through YAP/TAZ-PI3K-Akt pathway in endometrial carcinoma

Wei

Hou

et al. 2023

Cell Death Discov.

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Progestin resistance is a problem for patients with endometrial carcinoma (EC) who require conservative treatment with progestin, and its underlying mechanisms remain unclear. YAP and TAZ (YAP/TAZ), downstream transcription coactivators of Hippo pathway, promote viability, metastasis and also drug resistance of malignant tumors. According to our microarray analysis, YAP/TAZ were upregulated in progestin resistant IshikawaPR cell versus progestin sensitive Ishikawa cell, which implied that YAP/TAZ may be a vital promotor of resistance to progestin. We found YAP/TAZ had higher expression levels among the resistant tissues than sensitive tissues. In addition, knocking down YAP/TAZ decreased cell viability, inhibited cell migration and invasion and increased the sensitivity of IshikawaPR cell to progestin. On the contrary, overexpression of YAP/TAZ increased cell proliferation, metastasis and promoted progestin resistance. We also confirmed YAP/TAZ were involved in progestin resistant process by regulating PI3K-Akt pathway. Furthermore, Verteporfin as an inhibitor of YAP/TAZ could increase sensitivity of IshikawaPR cells to progestin in vivo and in vitro. Our study for the first time indicated that YAP/TAZ play an important role in progestin resistance by regulating PI3K-Akt pathway in EC, which may provide ideas for clinical targeted therapy of progestin resistance.

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“…Mutations in inhibitory modulators of Hippo signaling, including AJUBA and FATs, was found in ESCC. Although a few studies reported a different requirement of YAP or TAZ in different context, both the gene amplifications of YAP/TAZ were found in ESCC samples [5,6]. Several molecular biological studies have shown that depletion of YAP and TAZ can inhibit ESSC growth [7].…”

Section: Introductionmentioning

confidence: 99%

USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP

et al. 2022

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Esophageal squamous carcinoma (ESCC) is the major subtype of esophageal cancer in China, accounting for 90% of cases. Recent studies revealed that abnormalities in the Hippo/YAP axis are pervasive in ESCC and are recognized as the important driver of ESCC progression. Since the activity of Hippo signaling is controlled by phosphorylation cascade, it is a mystery why the major effector YAP is still over-activated when the cascade is inhibited. Several studies suggested that in addition to phosphorylation, other protein modifications such as ubiquitination also play important roles in manipulating Hippo/YAP signaling activity. Since YAP protein stability is controlled via an appropriate balance between E3 ubiquitin ligases and deubiquitinases, we performed deubiquitinase siRNA screening and identified USP36 as a deubiquitinase significantly related to Hippo/YAP signaling activity and ESCC progression. USP36 expression was elevated in ESCC samples and correlated with poor differentiation. USP36 expression was correlated with YAP protein levels in ESCC samples. Molecular studies demonstrated that USP36 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. In conclusion, our study revealed a novel deubiquitinase in regulating Hippo signaling in ESCC, which could be an encouraging drug target for Hippo-driven ESCC.

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YAP and TAZ: Monocorial and bicorial transcriptional co-activators in human cancers

Cited by 16 publications

References 148 publications

A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming

A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming

Verteporfin reverses progestin resistance through YAP/TAZ-PI3K-Akt pathway in endometrial carcinoma

USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP

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