Dataset Information

Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer.

ABSTRACT: YAP (gene symbol YAP1) as a potential oncoprotein, is positively correlated with the malignancy of various tumors. However, overexpression of YAP alone in multiple normal tissue cells has failed to induce tumor formation and the underlying mechanism is poorly understood. Herein, we show that YAP activation directly induces transcription of its negative regulator, SAV1, to constitute a negative feedback loop, which plays a vital role in maintaining lung epithelial cell homeostasis and was dysregulated in non-small cell lung cancer (NSCLC). Notably, smoking promotes the hypermethylation of the SAV1 promoter region, which disrupts YAP negative feedback by inactivating the Hippo pathway. Besides, exogenous overexpression of SAV1 can act as a traffic protein, activating the Hippo signaling and concurrently inhibiting the WNT pathway to decrease cancer cell growth. Furthermore, using the lung cancer organoids, we found that lentivirus-mediated SAV1 gene transfer combined with methylation inhibitor and YAP-TEAD inhibitor is a potential feasible clinical medication regimen for the lung cancer patient, especially among the smoking population. Thus, this SAV1 mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP regulation and as a potential target of gene therapy for the smoking NSCLC population.

SUBMITTER: Liu T

PROVIDER: S-EPMC9295071 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer.

Liu Ting T Guo Wei W Luo Kai K Li Lei L Dong Jing J Liu Meijun M Shi Xingyuan X Wang Zhiyuan Z Zhang Jianlei J Yin Jiang J Qiu Ni N Lu Minying M Chen Danyang D Jia Xiaoting X Liu Hao H Gu Yixue Y Xiong Yan Y Zheng Guopei G Xu Gang G He Zhimin Z Zhang Zhijie Z

International journal of biological sciences 20220711 11

YAP (gene symbol <i>YAP1</i>) as a potential oncoprotein, is positively correlated with the malignancy of various tumors. However, overexpression of YAP alone in multiple normal tissue cells has failed to induce tumor formation and the underlying mechanism is poorly understood. Herein, we show that YAP activation directly induces transcription of its negative regulator, SAV1, to constitute a negative feedback loop, which plays a vital role in maintaining lung epithelial cell homeostasis and was ...[more]

PMID: 35864957

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Dataset Information

Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer.

Publications

Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer.

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