identification-transcription-factor-regulators-using-medium

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Transcription factors can alter the expression of numerous target genes that influence a variety of downstream processes making them good targets for ...

Albany Medical College

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.

When properly employed, targeted therapies are effective cancer treatments. However, the development of such therapies requires the identification of targetable drivers of cancer development and metastasis. The expression and nuclear localization of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are increased in many human cancers, and experimental evidence indicates that aberrant YAP or TAZ activation drives tumor formation and metastasis. Although these findings make YAP and TAZ appealing therapeutic targets, both have important functions in adult tissues, so directly targeting them could cause adverse effects. The identification of pathways active in cancer cells and required for YAP/TAZ activity could provide a way to inhibit YAP and TAZ. Here, we show that SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes. In contrast, SRC inhibition or knockdown repressed both YAP/TAZ activity and the expression of YAP/TAZ-regulated genes. We also show that SRC increases the activity of YAP and TAZ by repressing large tumor suppressor homolog (LATS), and we identify the GTPase-activating protein GIT ArfGAP 1 (GIT1) as an SRC effector that regulates both YAP and TAZ. Importantly, we demonstrate that SRC-mediated YAP/TAZ activity promotes tumor growth and enhances metastasis and that SRC-dependent tumor progression depends, at least in part, on YAP and TAZ. Our findings suggest that therapies targeting SRC could help manage some YAP/TAZ-dependent cancers.

Article	Year
YAP/TAZ Activation as a Target for Treating Metastatic Cancer. Cancers\| PubMed ID: 29642615	2018
SRC tyrosine kinase activates the YAP/TAZ axis and thereby drives tumor growth and metastasis. The Journal of biological chemistry\| PubMed ID: 30559289	2019

Yuxuan Xiao

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