Abstract 5825: TM4SF19 regulates oxidative stress-dependent YAP transcription in HNSCC

Abstract 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.