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Int J Biol Sci 2023; 19(8):2458-2474. doi:10.7150/ijbs.79965 This issue Cite

Research Paper

YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer

Yue Ning1, Hongmei Zheng1, Yang Yang1, Hongjing Zang1, Weiyuan Wang4, Yuting Zhan1, Haihua Wang1, Jiadi Luo1, Qiuyuan Wen1, Jinwu Peng4, Juanjuan Xiang3, Songqing Fan1,2✉

1. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
2. Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
3. Cancer Research Institute, Central South University, Changsha, Hunan, China.
4. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

✉ Corresponding author: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China, E-mail: songqingfanedu.cn.

Citation:
Ning Y, Zheng H, Yang Y, Zang H, Wang W, Zhan Y, Wang H, Luo J, Wen Q, Peng J, Xiang J, Fan S. YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer. Int J Biol Sci 2023; 19(8):2458-2474. doi:10.7150/ijbs.79965. https://www.ijbs.com/v19p2458.htm
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Abstract

Graphic abstract

YAP1 is a well-known core effector of the Hippo pathway in tumors, but its potential role in osimertinib resistance remained unexplored. Our study provides evidence that YAP1 acts as a potent promoter of osimertinib resistance. By inhibiting YAP1 with a novel inhibitor, CA3, and combining it with osimertinib, we observed a significant suppression of cell proliferation and metastasis, induction of apoptosis and autophagy, and a delay in the emergence of osimertinib resistance. Interestingly, CA3 combined with osimertinib executed its anti-metastasis and pro-tumor apoptosis in part through autophagy. Mechanistically, we found that YAP1, in collaboration with YY1, transcriptionally represses DUSP1, leading to the dephosphorylation of the EGFR/MEK/ERK pathway and YAP1 phosphorylation in osimertinib-resistant cells. Our results also validate that CA3, in combination with osimertinib, executes its anti-metastasis and pro-tumor apoptosis partly through autophagy and the YAP1/DUSP1/EGFR/MEK/ERK regulatory feedback loop in osimertinib-resistant cells. Remarkably, our findings illustrate that YAP1 protein is upregulated in patients after osimertinib treatment and osimertinib resistance. Overall, our study confirms that the YAP1 inhibitor CA3 increases DUSP1 with concomitant activation of the EGFR/MAPK pathway and induces autophagy to enhance the efficacy of third-generation EGFR-TKI treatments for NSCLC patients.

Keywords: YAP1, Hippo pathway, Osimertinib, EGFR-TKI, Autophagy

Citation styles

APA
Ning, Y., Zheng, H., Yang, Y., Zang, H., Wang, W., Zhan, Y., Wang, H., Luo, J., Wen, Q., Peng, J., Xiang, J., Fan, S. (2023). YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer. International Journal of Biological Sciences, 19(8), 2458-2474. https://doi.org/10.7150/ijbs.79965.

ACS
Ning, Y.; Zheng, H.; Yang, Y.; Zang, H.; Wang, W.; Zhan, Y.; Wang, H.; Luo, J.; Wen, Q.; Peng, J.; Xiang, J.; Fan, S. YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer. Int. J. Biol. Sci. 2023, 19 (8), 2458-2474. DOI: 10.7150/ijbs.79965.

NLM
Ning Y, Zheng H, Yang Y, Zang H, Wang W, Zhan Y, Wang H, Luo J, Wen Q, Peng J, Xiang J, Fan S. YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer. Int J Biol Sci 2023; 19(8):2458-2474. doi:10.7150/ijbs.79965. https://www.ijbs.com/v19p2458.htm

CSE
Ning Y, Zheng H, Yang Y, Zang H, Wang W, Zhan Y, Wang H, Luo J, Wen Q, Peng J, Xiang J, Fan S. 2023. YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer. Int J Biol Sci. 19(8):2458-2474.

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