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Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here we sought to systematically characterize the division of labor between YAP and TAZ in non–small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Representative NSCLC cell lines as well as patient-derived data showed that the two paralogs orchestrated nonoverlapping transcriptional programs in this cancer type. YAP preferentially regulated gene sets associated with cell division and cell-cycle progression, whereas TAZ preferentially regulated genes associated with extracellular matrix organization. Depletion of YAP resulted in growth arrest, whereas its overexpression promoted cell proliferation. Likewise, depletion of TAZ compromised cell migration, whereas its overexpression enhanced migration. The differential effects of YAP and TAZ on key cellular processes were also associated with differential response to anticancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of patients with lung cancer for anticancer therapies.Significance:Thease findings show that oncogenic paralogs YAP and TAZ have distinct roles in NSCLC and are associated with differential response to anticancer drugs, knowledge that may assist lung cancer therapy decisions.

List of 142 YAP-differential drugs and 38 TAZ-differential drugs in LUAD cells. Each row is a drug, and each column specifies additional information, including dose used in the screen, drug targets, indication, clinical phase and the p-value of the comparison.

Sequences of siRNAs and primers used in this study.

Gene Ontology results of either the YAP-correlated or TAZ-correlated genes in LUAD TCGA, determined by Metascape.

Supplementary Figures

Gene ontology results of either YAP-regulated or TAZ-regulated genes from H1299 RNA-seq analysis, determined by Metascape.

Supplementary Figure 4 from Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Supplementary Figure 1 from Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Supplementary Figure 2 from Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Supplementary Figure 3 from Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Supplementary Figure Legends 1-4 from Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Paralogs originating from a gene duplication event can diverge and accumulate changes that contribute to a division of labor. Therefore, we wished to explore differential activities of YAP and TAZ. Traditionally, research has tended to consider YAP and TAZ as functionally redundant transcriptional cofactors, with similar biologic impact. However, there is growing evidence that each of them possesses distinct attributes. Hence, it is of great interest to find out whether YAP and TAZ have nonredundant involvement in cancer. Lung cancer is the leading cause of cancer-related deaths worldwide. Despite significant progress, the 5-year survival is still lower than 15%. Therefore, there is an urgent need for novel lung cancer biomarkers. Recent evidence suggests that YAP/TAZ play important roles in lung tumorigenesis. We explored differences in the transcriptional programs regulated by YAP and TAZ in lung adenocarcinoma cells, and the physiologic implications of such differences. Towards this aim, we performed RNA-sequencing in lung cancer cells following knockdown of either YAP or TAZ. Our analysis revealed a broad spectrum of expression patterns, including genes that are regulated preferentially by either YAP, TAZ, or both. Interestingly, a group of genes related to extracellular matrix remodeling was substantially regulated by TAZ but not YAP, while cell cycle- and proliferation-related genes were affected mainly by YAP but not TAZ. These differences in gene regulation correlated with functional differences between YAP and TAZ. Knockdown of TAZ strongly affected cell migration, whereas depletion of YAP had only mild effects on migration. Conversely, YAP silencing resulted in reduced proliferation compared to TAZ silencing. Importantly, YAP- and TAZ-dependent transcriptomes were correlated to lung cancer patient survival. In summary, our findings suggest that YAP and TAZ have distinct but complementary roles, which are associated with different cancer features. Hopefully, the identification of different activities and downstream effects of YAP and TAZ may enable more refined stratification of lung cancers and provide clues for the development of more effective targeted therapies. Citation Format: Michal Shreberk-Shaked, Bareket Dassa, Silvia Di Agostino, Yarden Nuriel, Noa Wigoda, Ron Rotkopf, Giovanni Blandino, Yael Aylon, Moshe Oren. Division of labor between YAP and TAZ in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B43.

Mutations in the p53 tumor suppressor are the most common genetic events in human cancer. These mutations not only result in a loss of wild-type p53 activity, but can also lead to a gain of new oncogenic properties. Understanding how these gained functions are regulated is in its infancy. In this study, we show that the promyelocytic leukemia (PML) protein is an important regulator of mutant p53. We show that PML interacts with mutant p53. Importantly, PML enhances the transcriptional activity of mutant p53. Unexpectedly, PML is required for the proliferation and colony formation of cancer cells bearing mutant p53. Down-regulation of PML expression inhibits the growth of mutant p53-expressing cancer cells, predominantly by promoting cell cycle arrest. Our results suggest that the tumor suppression function of PML depends on the status of p53. In the context of mutant p53, PML enhances its cancer-promoting activities. [Cancer Res 2009;69(11):4818–26]

Che-1 is a RNA polymerase II binding protein involved in the regulation of gene transcription, and in response to DNA damage promotes p53 transcription. In this study, we investigated whether Che-1 regulates mutant p53 expression. We found that Che-1 is required for sustaining mutant p53 expression in several cancer cell lines, and Che-1 depletion by siRNA induces apoptosis both in vitro and in vivo. Notably, loss of Che-1 activates DNA damage checkpoint response and induces transactivation of p73. Therefore, these findings suggest a new therapeutic approach that allowing simultaneous modulation of p73 and mutant p53 levels might be used to target the large fraction of human tumors harboring p53 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2983.