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

Liu, Ting; Guo, Wei; Luo, Kai; Li, Lei; Dong, Jing; Liu, Meijun; Shi, Xingyuan; Wang, Zhiyuan; Zhang, Jianlei; Yin, Jiang; Qiu, Ni; Lu, Minying; Chen, Danyang; Jia, Xiaoting; Liu, Hao; Gu, Yixue; Xiong, Yan; Zheng, Guopei; Xu, Gang; He, Zhimin; Zhang, Zhijie

doi:10.7150/ijbs.73428

Theranostics

International Journal of Medical Sciences

Nanotheranostics

Journal of Cancer

Journal of Genomics

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Int J Biol Sci 2022; 18(11):4497-4512. doi:10.7150/ijbs.73428 This issue Cite

Research Paper

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

Ting Liu^1#, Wei Guo^1#, Kai Luo^1#, Lei Li¹, Jing Dong¹, Meijun Liu¹, Xingyuan Shi², Zhiyuan Wang², Jianlei Zhang¹, Jiang Yin¹, Ni Qiu¹, Minying Lu¹, Danyang Chen¹, Xiaoting Jia¹, Hao Liu¹, Yixue Gu¹, Yan Xiong², Guopei Zheng^1,3, Gang Xu^1✉, Zhimin He^1✉, Zhijie Zhang^1✉

1. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of “Translational Medicine on Malignant Tumor Treatment”, Guangzhou city, Guangdong, P. R. China.
2. Department of Central Laboratory, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P. R. China.
3. The State Key Laboratory of Respiratory, Guangzhou, Guangdong, P. R. China.
#These authors contributed equally to this work.

Citation:

Liu T, Guo W, Luo K, Li L, Dong J, Liu M, Shi X, Wang Z, Zhang J, Yin J, Qiu N, Lu M, Chen D, Jia X, Liu H, Gu Y, Xiong Y, Zheng G, Xu G, He Z, Zhang Z. Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer. Int J Biol Sci 2022; 18(11):4497-4512. doi:10.7150/ijbs.73428. https://www.ijbs.com/v18p4497.htm

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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.

Keywords: SAV1, YAP, Lung Cancer, Methylation, Tobacco smoking

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APA

Liu, T., Guo, W., Luo, K., Li, L., Dong, J., Liu, M., Shi, X., Wang, Z., Zhang, J., Yin, J., Qiu, N., Lu, M., Chen, D., Jia, X., Liu, H., Gu, Y., Xiong, Y., Zheng, G., Xu, G., He, Z., Zhang, Z. (2022). Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer. International Journal of Biological Sciences, 18(11), 4497-4512. https://doi.org/10.7150/ijbs.73428.

ACS

Liu, T.; Guo, W.; Luo, K.; Li, L.; Dong, J.; Liu, M.; Shi, X.; Wang, Z.; Zhang, J.; Yin, J.; Qiu, N.; Lu, M.; Chen, D.; Jia, X.; Liu, H.; Gu, Y.; Xiong, Y.; Zheng, G.; Xu, G.; He, Z.; Zhang, Z. Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer. Int. J. Biol. Sci. 2022, 18 (11), 4497-4512. DOI: 10.7150/ijbs.73428.

NLM

CSE

Liu T, Guo W, Luo K, Li L, Dong J, Liu M, Shi X, Wang Z, Zhang J, Yin J, Qiu N, Lu M, Chen D, Jia X, Liu H, Gu Y, Xiong Y, Zheng G, Xu G, He Z, Zhang Z. 2022. Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer. Int J Biol Sci. 18(11):4497-4512.

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