The transcriptional cofactor YAP and its inhibitory regulators, Hippo kinases and adapter proteins, constitute an evolutionarily conserved signaling pathway that controls organ size and cell fate. The activity of the Hippo-YAP pathway is determined by a variety of intracellular and intercellular cues, such as cell polarity, junctions, density, mechanical stress, energy status, and growth factor signaling. Recent studies have demonstrated that YAP can induce the expression of a set of genes that allow cancer cells to gain a survival advantage and aggressive behavior. Comprehensive genomic studies have revealed frequent focal amplifications of the YAP locus in human carcinomas, including head and neck squamous cell carcinoma (HNSCC). Moreover, FAT1, which encodes an upstream component of Hippo signaling, is one of the most commonly altered genes in HNSCC. In this review, we discuss the causes and functional consequences of YAP dysregulation in HNSCC. We also address interactions between YAP and other oncogenic drivers of HNSCC.
The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.
Objective: JBTS17 is a major gene mutated in ciliopathies such as Joubert syndrome and oral-facial-digital syndrome type VI. Most patients with loss of function mutations in JBTS17 exhibit cerebellar vermis hypoplasia and brainstem malformation. However, some patients with JBTS17 mutations show microcephaly and abnormal gyration. We examined potential roles of JBTS17 in neurogenesis to understand the pathological mechanism of JBTS17-related cortical abnormalities. Methods: We examined subcellular localization and cell-cycle-dependent expression of JBTS17 proteins using anti-JBTS17 antibodies and JBTS17 expression vectors. We also performed knockdown experiments to determined roles of JBTS17 in human cells, and demonstrated mitotic functions of JBTS17 using immunostaining and live imaging. We examined the involvement of JBTS17 in cortical neurogenesis using a mouse in utero electroporation technique. Results: We found that JBTS17 localizes to the kinetochore and the level of JBTS17 is regulated by cell-cycle-dependent proteolysis. Depletion of JBTS17 disrupts chromosome alignment and spindle pole orientation, resulting in mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex interferes with the mitotic progression of neural progenitors and the migration of postmitotic neurons. Interpretation: LIS1 is implicated in lissencephaly, but altered dosage of LIS1 has been also associated with microcephaly syndromes. Our results suggest that JBTS17 contributes to mitotic progression by interacting with LIS1, and abnormal mitosis is an underlying mechanism of the microcephaly phenotype in JBTS17-related ciliopathies. We propose that understanding extraciliary roles of ciliopathy proteins is important to elucidate pathological mechanisms underlying diverse ciliopathy phenotypes.
Head-and-neck squamous cell carcinoma (HNSCC), which arises from epithelial cells in mucosal surfaces of the upper aerodigestive tract, is the sixth leading cancer worldwide with 40-50% mortality rates. YAP is a transcriptional regulator that plays important roles in cancer cell proliferation and survival. HNSCC shows the highest levels of YAP gene expression among various types of human cancers. However, the molecular mechanisms explaining upregulation of YAP expression in HNSCC are poorly understood. Excessive consumption of tobacco and alcohol are classical risk factors of HNSCC. Tobacco and alcohol generates metabolites that increase reactive oxygen species (ROS) to abnormally high levels. It is not known whether YAP expression and function are interlinked with the oxidative stress response in HNSCC. Here, we aimed to elucidate the mechanism of YAP upregulation involved in the progression of HNSCC under conditions of oxidative stress. To identify candidates for YAP expression regulators in HNSCC, we analyzed whole-genome siRNA library screening data and TCGA genomics data. We performed loss-of-function and gain-of-function experiments to elucidate the molecular mechanism of TM4SF19, which is the top candidate for mediating transcriptional regulation of YAP in HNSCC. TM4SF19 is one of the transmembrane 4 L six family proteins that have topological similarities to tetraspanins, but little is known about its biological function. We found TM4SF19 controls the expression of YAP gene by regulating GABPβ1, a subunit of the GABP transcription factor complex, which is known to bind and activate YAP gene promoter. We observed that the depletion of TM4SF19 reduced GAPBPβ1, thereby decreasing the transcriptional activity of GABP complex. Importantly, we observed that TM4SF19 was dimerized in response to oxidative stress and consequently mediates the upregulation of YAP transcription by ROS elevation. We further show that TM4SF19 knockdown significantly reduces key characteristics of malignant cells, such as active proliferation and migration. Our results suggest that TM4SF19 is not only a novel transcriptional regulator of YAP but also a strong therapeutic target to suppress the oncogenic activity of YAP, and also provide new clue to understand HNSCC tumorigenesis involving YAP and oxidative stress. Citation Format: Eunbie Shin, Joon Kim. TM4SF19 regulates oxidative stress-dependent YAP transcription in HNSCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5825.
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